Dry powder inhalation system for transpulmonary administration

ABSTRACT

The present invention provides a novel dry powder inhalation system suitable for transpulmonary administration. The dry powder inhalation system of the invention characterized by using a combination of:
         (1) a vessel housing a freeze-dried composition that contains a single dose of an active ingredient, and has:
           (i) a non-powder cake-like form,   (ii) a disintegration index of 0.015 or more, and   (iii) a property of becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and   
           (2) a device comprising means capable of applying said air impact to the freeze-dried composition in said vessel, and means for discharging the powder-form freeze-dried composition that has been made into fine particles.

This is a division of application Ser. No. 10/170,339, filed Jun. 14,2002 now U.S. Pat. No. 7,448,379 and claims priority to Japanese PatentApplication No. 2002-111131, filed Apr. 12, 2002, Japanese PatentApplication No. 2001-400871, filed Dec. 28, 2001, and Japanese PatentApplication No. 2001-182504, filed Jun. 15, 2001, all of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel dry powder inhalation systemsuitable for transpulmonary administration. More specifically, thepresent invention relates to a dry powder inhalation system fortranspulmonary administration according to which a freeze-driedcomposition provided housed in a vessel can be prepared into a formsuitable for transpulmonary administration by being made into fineparticles at the time of use, and administered by inhalation as is.

Furthermore, the present invention encompasses the following inventionsrelated to the dry powder inhalation system for transpulmonaryadministration. Specific examples of these inventions include afreeze-dried composition which can be made into fine particle powdersuitable for transpulmonary administration (dry powdered preparation fortranspulmonary administration) at the time of use, a device(apparatus/implement) used in preparation and inhalation of the drypowdered preparation for transpulmonary administration, a method forproducing the dry powdered preparation for transpulmonaryadministration, a method for transpulmonary administration by inhalationusing the freeze-dried composition and use of a freeze-dried compositionfor preparing a dry powdered preparation for transpulmonaryadministration at the time of use.

Hereinafter, in this specification, the term “fine particles” includespulverized powder (particle powder).

BACKGROUND ART

In general, with regard to transpulmonary administration, it is knownthat the active ingredient contained in a medicine can be delivered intothe lungs efficiently by making the mean particle diameter of the activeingredient be 10 microns or less, preferably 5 microns or less. Thecurrent situation with conventional inhalations for transpulmonaryadministration is thus that, to make the medicine have a particlediameter suitable for transpulmonary administration in advance, fineparticles are prepared by a spray drying method, a jet milling method orthe like, and possibly further processing is carried out, and then thefine particles are provided filled into a dry powder inhaler.

Specifically, Japanese Unexamined Patent Publication No. 1999-171760discloses three types of powdered inhalation, namely (1) a preparationcomprising a powder-form composition comprising only medicinal fineparticles filled into a suitable vessel, (2) a preparation comprising apowder-form composition in which medicinal fine particles have beengranulated gently to form a relatively large particle diameter filledinto a suitable vessel, and (3) a preparation comprising a powder-formcomposition comprising mixed particles in which medicinal fine particlesand vehicle particles (lactose etc.) having a particle diameter largerthan the medicinal fine particles are mixed together uniformly filledinto a suitable vessel. Moreover, it is disclosed that if these powderedinhalations are administered into the respiratory tract, then thebehavior shown is that with (1) the medicinal fine particles in thecomposition reach the lower respiratory tract, for example the tracheaand the bronchi, and are deposited here, with (2) the granulatedmedicine separates into fine particles in flight in the respiratorytract, and the medicinal fine particles produced reach the lowerrespiratory tract, for example the trachea and the bronchi, and aredeposited here, and with (3) the vehicle is deposited in the oralcavity, on the pharynx or on the larynx, and the medicinal fineparticles only reach the lower respiratory tract, for example thetrachea and the bronchi, and are deposited here.

In this way, with a conventional powdered inhalation for transpulmonaryadministration, the ingredient to be inhaled is made into desirable fineparticles in advance, and then these fine particles, or else these fineparticles further processed by some method, are filled into a dry powderinhaler, and transpulmonary administration is carried out using this.

To make a low-molecular-weight drug into fine particles, a spray dryingmethod (for example, a method disclosed in Japanese Unexamined PatentPublication No. 1999-171760), a jet milling method (for example, amethod disclosed in Japanese Unexamined Patent Publication No.2001-151673) or the like is usually used. The jet milling methodcomprises applying an air impact having an air flow rate of at least1000 L/min and an air speed not less than the sonic speed to alow-molecular-weight drug to make the drug into fine particles. Nomethod is known which makes the drug into fine particles by a low airimpact.

For a high-molecular-weight drug such as a peptide or protein, on theother hand, for example a method in which a spray solution of amedicinal stock liquid containing additives is subjected to spraydrying, thus making the stock liquid into fine particles having a meanparticle diameter of 5 microns or less in one step, and then these fineparticles are filled into a dry powder inhaler (spray drying method: WO95/31479), and a method in which a peptide or protein is freeze-driedalong with additives, and then the freeze-dried composition is made intofine particles by jet milling or the like, and these fine particles arefilled into a dry powder inhaler (freeze drying-jet milling method: WO91/16038) are known.

However, conventional powdered inhalations for transpulmonaryadministration prepared by the above-mentioned spray drying method orfreeze drying-jet milling method are not necessarily ideal preparationsfor high-molecular-weight drugs such as peptides and proteins inparticular. For example, as shown by the disclosure in WO 95/31479 thatabout 25% deactivation of interferon occurs during the spray dryingprocess, it is anticipated that if the spray drying method is used, thenproteins and the like will be deactivated in the manufacturing processand the activity of the drug will thus decrease.

No method is known which makes a high-molecular-weight drug into fineparticles by a low air impact, the same as a low-molecular-weight drug.

Moreover, with both the spray drying method and the freeze drying-jetmilling method, an operation is required in which the fine powderprepared is collected from the spray drying apparatus or jet millingapparatus and is subdivided and filled into vessels. It is thusinevitable that, accompanying this operation, problems will arise suchas the yield of the preparation decreasing due to collection or fillingloss and the cost rising correspondingly, and the preparation beingcontaminated with impurities. Moreover, in general it is difficult tosubdivide and fill the powder in small amounts with good accuracy. Ifthe spray drying method or the freeze drying-jet milling method, forwhich such subdividing and filling of small amounts in powder form isessential, is used, then it is thus necessary to establish a method offilling with small amounts and good accuracy of powder. In actual fact,details of a system, apparatus and method for filing with a fine powderare disclosed in U.S. Pat. No. 5,826,633.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to solve the various problemsof the above-mentioned conventional powdered inhalations fortranspulmonary administration. Specifically, it is an object of thepresent invention to provide a novel preparation system andadministration system that enables a freeze-dried composition that hasbeen housed in vessels in advance subdivided into single doses of activeingredient to be made into fine particles down to a particle diametersuitable for transpulmonary administration by inhalation in the vesselat the time of usage, and then be used for transpulmonary administrationas is.

The present inventors carried out assiduous studies to attain the aboveobject, and as a result discovered that if a pharmacologically activesubstance is filled as a liquid into vessels subdivided into requiredamounts and then freeze-dried, then the non-powder-form freeze-driedcomposition thus prepared can unexpectedly be made into fine particlesby a relatively low air impact while still housed in the vessel. Basedon this knowledge, the present inventors carried out further studies,and as a result discovered that by using a freeze-dried composition, asingle dose of which has been housed in a non-powder form in a vessel,combined with a device comprising means for introducing air at aprescribed speed and flow rate into the vessel so as to be capable ofapplying a prescribed air impact to the composition, and means fordischarging from the vessel the powdered composition that has been madeinto fine particles, then the freeze-dried preparation can be preparedinto a fine particle powder form suitable for transpulmonaryadministration easily by a user at the time of use (specifically, at thetime of inhalation), and the fine particle powder can be administered byinhalation as is. Moreover, it was verified that, according to thistranspulmonary administration system, all of the previously mentionedproblems of conventional powdered inhalations for transpulmonaryadministration can be solved.

That is, according to the above-mentioned transpulmonary administrationsystem of the present invention, it is not necessary to collect thepharmaceutical preparation in a powder form and then fill it intovessels, but rather preparation is carried out by accurately fillingeach vessel with liquid and then carrying out freeze drying, and hencethe transpulmonary administration system can be used for transpulmonaryadministration with an extremely high accuracy and high preparationyield, and without the problem of contamination. Moreover, according tothe above-mentioned administration system, active ingredients such asproteins or peptides are not exposed to high temperature in themanufacturing process as is the case with the spray drying method andthe like, and hence there is no problem of the pharmacological activitydropping due to exposure to high temperature. Therefore, theadministration system of the present invention is an extremely usefulsystem in particular with pharmacologically active substances such aspeptides and proteins that are expensive drugs, since the manufacturingcost can be reduced.

Moreover, according to the dry powder inhalation system of the presentinvention, an extremely high fine particle fraction (the amount of thedrug reaching the lungs: fine particle fraction, respirable fraction) isobtained, and hence the drug can be delivered into the lungsefficiently.

The dry powder inhalation system of the invention is characterized byusing a freeze-dried composition in a non-powder cake-like form as apreparation for manufacturing a powdered preparation for transpulmonaryadministration. The dry powder inhalation system of the invention inwhich the freeze-dried composition in a cake-like form is applied to adry powder inhaler is capable of achieving a significantly higher fineparticle fraction compared to the case where a preparation made intofine particle powder having a size suitable for transpulmonaryadministration using a method employed for powder inhalants heretoforeknown, such as a jet milling method or a spray drying method, is appliedto a dry powder inhaler of the invention.

For such reasons, the dry powder inhalation system of the presentinvention can be ranked as a high-performance transpulmonaryadministration system.

The present invention was developed based on this knowledge.

(I) The present invention includes the following dry powder inhalationsystem for transpulmonary administration.

The dry powder inhalation system for transpulmonary administrationcomprises a combination of a freeze-dried composition that exists in anon-powder form in a vessel and is capable of being made into fineparticles having a mean particle diameter of 10 microns or less withinthe vessel after applying a prescribed air impact to the freeze-driedcomposition in the vessel, a device capable of applying theabove-mentioned air impact to the freeze-dried composition in thevessel, and a device capable of discharging the thus obtained fineparticles.

The following can be put forward as specific embodiments of this drypowder inhalation system for transpulmonary administration.

-   -   A dry powder inhalation system for transpulmonary        administration, using a combination of:

(1) a vessel housing a freeze-dried composition that contains a singledose of an active ingredient, and has:

-   -   (i) a non-powder cake-like form,    -   (ii) a disintegration index of 0.015 or more, and    -   (iii) a property of becoming fine particles having a mean        particle diameter of 10 microns or less or a fine particle        fraction of 10% or more upon receiving an air impact having an        air speed of at least 1 m/sec and an air flow rate of at least        17 ml/sec; and

(2) a device having means capable of applying said air impact to thefreeze-dried composition in said vessel and means for discharging thepowder-form freeze-dried composition that has been made into fineparticles.

(II) Furthermore, the present invention includes the followingfreeze-dried compositions pulverized into fine particles having aparticle size suitable for transpulmonary administration using an airimpact.

-   -   A freeze-dried composition for transpulmonary administration        having the following properties (i) to (iii):        -   (i) has a non-powder cake-like form,        -   (ii) has a disintegration index of 0.015 or more, and        -   (iii) becomes fine particles having a mean particle diameter            of 10 microns or less or a fine particle fraction of 10% or            more upon receipt of an air impact having an air speed of at            least 1 m/sec and an air flow rate of at least 17 ml/sec.

(III) Furthermore, the present invention includes the following drypowder inhalers usable in the dry powder inhalation system fortranspulmonary administration.

The inhalers are used for administering the fine particles obtained byapplying an air impact to a freeze-dried composition that has beenhoused in a non-powder form in a vessel to a user by inhalation.Specific examples of such inhalers comprise {circle around (1)} meanscapable of applying an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec to the freeze-driedcomposition in the vessel, and {circle around (2)} means for dischargingthe powder-form freeze-dried composition that has been pulverized intofine particles. More specifically, the inhalers encompass jet type drypowder inhalers as in (a) below and self-inhaling type dry powderinhalers as in (b) below.

(a) Jet Type Dry Powder Inhaler: Active Powder Inhaler

A device used in making a freeze-dried composition that has been housedin a non-powder form in a vessel into fine particles and administeringthe obtained fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding means for feeding airinto the air jet flow path of the needle part, and an inhalation portthat communicates with the discharge flow path,

and being constituted such that a stopper that seals up the vessel ispierced by the needle parts, thus communicating the air jet flow pathand the discharge flow path with the inside of the vessel, and air isjetted into the vessel from the air jet flow path using the airpressure-feeding means, thus breaking down the freeze-dried compositioninto fine particles by the impact of the jetted air, and discharging thefine particles obtained from the inhalation port via the discharge flowpath.

(b) Self-Inhaling Type Dry Powder Inhaler: Passive Powder Inhaler

A device used in making a freeze-dried composition that has been housedin a non-powder form in a vessel into fine particles and administeringthe obtained fine particles to a user, by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with the suction flow path,

and being constituted such that, in a state in which a stopper thatseals up the vessel has been pierced by the needle parts, through theinhalation pressure of a user, air in the vessel is inhaled from theinhalation port, and at the same time outside air flows into the vessel,which is now at a negative pressure, through the air introduction flowpath, and as a result the freeze-dried composition is pulverized intofine particles by the impact of the air flowing in, and the fineparticles obtained are discharged from the inhalation port through thesuction flow path.

(IV) Furthermore, the present invention includes the following methodsof manufacturing a powdered preparation for transpulmonaryadministration.

-   -   A method of manufacturing a dry powdered preparation for        transpulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec using a device capable of applying said air impactto the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more;

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of the air impact.

(V) Furthermore, the present invention includes the followingtranspulmonary administration methods characterized by using a drypowder inhalation system for transpulmonary administration as describedabove. According to the transpulmonary administration method, afreeze-dried composition that has been housed in a non-powder form in avessel is pulverized into a fine particle powder suitable fortranspulmonary administration at the time of use so that a user(patient) can administer the fine-particle-form powdered preparation byinhalation. The following embodiments are included in the administrationmethod.

-   -   A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more by applying an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec to the freeze-driedcomposition at the time of use, and

administering the resulting fine particle powder to a user byinhalation;

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of the air impact.

(VI) Furthermore, the present invention includes the following uses of afreeze-dried composition for transpulmonary administration.

-   -   Use of a freeze-dried composition for transpulmonary        administration by inhalation,

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of an air impact having an air speed of at least 1        m/sec and an air flow rate of at least 17 ml/sec, and being used        by pulverizing into fine particles having said mean particle        diameter or said fine particle fraction.

(VII) Furthermore, the following uses of a freeze-dried composition formanufacture of a dry powdered preparation for transpulmonaryadministration are included in the present invention.

-   -   Use of a freeze-dried composition for manufacture of a dry        powdered preparation for transpulmonary administration by        inhalation,

the freeze-dried composition having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of an air impact having an air speed of at least 1        m/sec and an air flow rate of at least 17 ml/sec, and being used        by pulverizing into fine particles having said mean particle        diameter or said fine particle fraction at the time of use.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view showing a dry powder inhaler (jet type 1) ofthe present invention disclosed as Embodiment 1. Note that, in thedrawing, the arrows indicate the flow of external air (likewise in FIGS.2 and 3 below).

Moreover, the meanings of the various reference numerals are as follows:1. vessel, 1 a. stopper, 2. freeze-dried composition, 3. air jet flowpath, 4. discharge flow path, 5. needle part, 6. inhalation port, 7. airintake member, 8. tubular safety cover, 9. air pressure-feeding means,10. bellows body, 11. intake valve, 12. intake port, 13. dischargevalve, 14. discharge port, 15. connecting port (likewise in FIGS. 2 to11 below).

FIG. 2 is a sectional view showing a dry powder inhaler (self-inhalingtype 1) of the present invention disclosed as Embodiment 2. Moreover,the meanings of the various reference numerals are as follows: 16.suction flow path, 17. air introduction flow path, 18. inhalation port,19. air intake member (likewise in FIG. 3 below).

FIG. 3 is a sectional view showing a dry powder inhaler (self-inhalingtype 2) of the present invention disclosed as Embodiment 3.

FIG. 4 is a perspective view showing a dry powder inhaler (self-inhalingtype 3) of the present invention disclosed as Embodiment 4. Moreover,the meanings of the reference numerals are as follows: 21. housing, 22.holder part, 27. lid, 28. window, 32. mouthpiece, 32 a. mouthpiece cap,39. connector (likewise in FIGS. 5 to 13 below).

FIG. 5 is a sectional view of the above-mentioned dry powder inhaler(self-inhaling type 3). Moreover, the meanings of the reference numeralsare as follows: 20. housing chamber, 21A. hinge, 23. guide part, 24.holder operating part, 26. housing main body, 29. introduction port, 30.check valve, 31. suction port, 33. partition part, 35. remover, 36.lever, 37. mechanism part, 39. connector, 40. hinge, 41. hinge (likewisein FIGS. 6 to 13 below).

FIG. 6( a) is a sectional view of part of the above-mentioned dry powderinhaler (self-inhaling type 3). (b) is a side view of the needle part ofthis dry powder inhaler. Moreover, the meanings of the referencenumerals are as follows: 16 a. tip opening of suction flow path 16, 17a. tip opening of air introduction flow path 17, 34. peripheral wallpart, 42. second introduction path, 42 a. introduction groove inpartition part 33, 42 b. introduction groove in peripheral wall part 34,43. gap, 44. one end of second introduction path 42, 45. other end ofsecond introduction path 42, 46. vent hole, 47. wall (likewise in FIGS.7 to 13 below).

FIGS. 7 to 10 are sectional views for explaining the operation of theabove-mentioned dry powder inhaler (self-inhaling type 3). Referencenumeral 25 indicates a removal/insertion port.

FIG. 11 is a perspective view of a dry powder inhaler (self-inhalingtype 4), which is another embodiment of the present invention. Referencenumeral 48 indicates an operator.

FIGS. 12 and 13 are perspective views of a dry powder inhaler(self-inhaling type 5) of another embodiment of the present invention.Reference numeral 49 indicates an operator.

FIG. 14 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 1.

FIG. 15 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 2.

FIG. 16 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 3.

FIG. 17 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 4.

FIG. 18 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 5.

FIG. 19 is a graph showing the particle size distribution of fineparticles jetted out from the dry powder inhaler in Example 6.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Dry Powder Inhaler

The dry powder inhaler used in the present invention is a device usedfor breaking down a freeze-dried preparation (freeze-dried composition)that has been housed in a non-powder form in a vessel into fineparticles in the vessel, and allowing a user to inhale the dry powderedpreparation.

By comprising {circle around (1)} means capable of applying an airimpact to the non-powder form freeze-dried composition in a degree suchthat the freeze-dried composition can be pulverized into fine particles,and {circle around (2)} means capable of administering to a user byinhalation the powder-form freeze-dried composition that has been madeinto fine particles, the device can carry out both breaking down of thefreeze-dried composition into fine particles and administration of thepowdered composition to a user by inhalation. Note that means {circlearound (1)} can also appreciated as means for introducing air having theabove-mentioned air impact into the vessel housing the freeze-driedcomposition. Moreover, means {circle around (2)} can also appreciated asmeans for discharging out of the vessel the powdered preparation thathas been made into fine particles in the vessel. In a dry powderinhalation system of the present invention, as long as the devicecomprises these means, either a conventional publicly-known device or adevice which will be developed in the future can also be used.

Specifically, the means {circle around (1)} can be realized byintroducing air capable of applying an air impact as above into thevessel housing the freeze-dried composition. Note that the means {circlearound (1)} can be altered into means capable of applying an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least17 ml/sec to the freeze-dried composition in the vessel.

By using the means {circle around (2)} or via this means, the drypowdered preparation, which has been prepared into a form suitable fortranspulmonary administration, can be administered by inhalation to theuser such as patient. Note that, for example a chamber or a flow pathsuch that the composition is made into fine particles or scattered maybe further provided in the means {circle around (2)}.

The device in question encompasses jet type dry powder inhalers as in(a) below and self-inhaling type dry powder inhalers as in (b) below.

(a) Jet Type Dry Powder Inhaler: Active Powder Inhaler

(a-1) A dry powder inhaler used in the making into fine particles andinhalation of a freeze-dried composition that has been housed in anon-powder form in a vessel,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding means for feeding airinto the air jet flow path of the needle part, and an inhalation portthat communicates with the discharge flow path,

and being constituted such that a stopper that seals up the vessel ispierced by the needle parts, thus communicating the air jet flow pathand the discharge flow path with the inside of the vessel, and air isjetted into the vessel from the air jet flow path using the airpressure-feeding means, thus breaking down the freeze-dried compositioninto fine particles by the impact of the jetted air, and discharging thefine particles obtained out from the inhalation port via the dischargeflow path.

(a-2) The dry powder inhaler described in (a-1) above, being constitutedsuch that the air pressure-feeding means is manually operated andcomprises a bellows body having an intake port equipped with an intakevalve and a discharge port equipped with a discharge valve, and bycontracting the bellows body and thus opening the discharge valve in astate in which the intake valve is closed, air in the bellows body ispressure-fed into the vessel through the air jet flow path of the needlepart which communicates with the discharge port, and by expanding thebellows body through an elastic restoring force in a state in which thedischarge valve is closed and the intake valve is open, air isintroduced into the bellows body.

(a-3) The dry powder inhaler described in (a-1) or (a-2) above, in whichthe air jet flow path and the discharge flow path are formed in a singleneedle part.

(b) Self-Inhaling Type Dry Powder Inhaler: Passive Powder Inhaler

(b-1) A dry powder inhaler used for inhaling fine particles obtained bybreaking down a freeze-dried composition that has been housed in anon-powder form in a vessel,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with the suction flow path,

and being constituted such that, in a state in which a stopper thatseals up the vessel has been pierced by the needle parts, through theinhalation pressure of a user, air in the vessel is inhaled from theinhalation port, and at the same time outside air flows into the vessel,which is now at a negative pressure, through the air introduction flowpath, and as a result the freeze-dried composition is broken down intofine particles by the impact of the air flowing in, and the fineparticles obtained are discharged from the inhalation port through thesuction flow path.

(b-2) The dry powder inhaler described in (b-1) above, being constitutedsuch that most part of the freeze-dried composition is made into fineparticles and discharged from the inhalation port through one inhalationof the user.

(b-3) The dry powder inhaler described in (b-1) or (b-2) above, in whichthe suction flow path and the air introduction flow path are formed in asingle needle part.

The means for introducing air into the vessel (means {circle around (1)}mentioned above) may be means for introducing air from the outside atnormal pressure. It is not necessary to use compressed air from a jetmill or the like. There are no limitations on the means for introducingair from the outside. For example, in the case where the jet type drypowder inhaler (active powder inhaler) described above is used, meansfor artificially introducing external air into the vessel by jetting canbe employed. In the case where the self-inhaling type dry powder inhaler(passive powder inhaler) is used, means for naturally introducingoutside air into the vessel by suction through negative pressure formedin the vessel when the user inhales can be employed. Moreover, in theformer case, i.e. in the jet type dry powder inhaler (active powderinhaler), the method of introducing external air into the vessel byjetting artificially may be manual or may be a method that is carriedout automatically using a machine.

The dry powder inhaler of the invention, regardless of the type of theinhaler, whether it is an active powder inhaler or a passive powderinhaler, is capable of breaking down the freeze-dried composition thathas been stored in non-powder form in the vessel into fine particlesusing an impact (jet pressure) of external air introduced into (flowinginto) the vessel by the air introduction means.

For example, a vessel, used for freeze-drying can be used here, with nolimitations on the material, shape etc. As the material, a plasticmainly including a polyolefin such as polyethylene, polypropylene orpolystyrene, glass, aluminum and the like can be given as examples.Moreover, as the shape, a circular cylinder, a cup shape, and apolygonal prism (polygonal pyramid) such as a triangular prism(triangular pyramid), a square prism (square pyramid), a hexagonal prism(hexagonal pyramid) or an octagonal prism (octagonal pyramid) can begiven as examples.

To obtain the effects efficiently, the volume of the vessel housing thefreeze-dried composition is in a range of 0.2 to 50 ml, preferably 0.2to 25 ml and more preferably 1 to 15 ml. Moreover, it is desirable to beused the trunk diameter of the vessel be 2 to 100 mm, preferably 2 to 75mm, more preferably 2 to 50 mm.

Moreover, the amount of the freeze-dried composition housed in thevessel is preferably an amount containing a unit dose (single dose) or aplurality of doses, specifically 2 to 3 doses, of the active ingredient.More preferably, it is an amount containing a unit dose (single dose) ofthe active ingredient. Moreover, the specific amount of the freeze-driedcomposition will vary according to the type and content of the activeingredient contained in the freeze-dried composition, and is selected asappropriate from amounts that can be inhaled, with there being noparticular limitation; nevertheless, the amount is generally 30 mg orless, preferably 20 mg or less, more preferable 10 mg or less,particularly preferably 5 mg or less.

Moreover, the air impact generated by the outside air introduced intothe vessel is stipulated through the air flow rate at which air flowsinto the vessel through at least one or a plurality of inhalations of aperson or the air speed thus generated. There is no particularlimitation on introducing external air with an air flow rate or airspeed greater than this, except of course that the durability of thevessel is a limitation. Generally the air flow rate for one inhalationof a person is 5 to 300 L/min, more specifically 10 to 200 L/min.Moreover, in the case of an dry powder inhaler, a device can be usedsuch that the amount of air jetted each time is 5 to 100 ml, preferably10 to 50 ml. Preferably, adjustment can be carried out such that an airimpact generated through an air speed of at least 1 m/sec is applied tothe surface of the freeze-dried composition filled in the vessel. A morepreferable air impact is an impact generated by an air speed of at least2 m/sec, a yet more preferable one is an impact generated by an airspeed of at least 5 m/sec, and a still more preferable one is an impactgenerated by an air speed of at least 10 m/sec. Here, there is noparticular limitation on the upper limit of the air impact, but animpact generated by an air speed of 300 m/sec can be given as anexample. The upper limit is preferably an impact generated through anair speed 250 m/sec, more preferably an impact generated through an airspeed 200 m/sec, yet more preferably an impact generated through an airspeed 150 m/sec.

There is no particular limitation on the air impact as long as it isgenerated by air having an air speed arbitrarily selected from the rangeextending from a lower limit to an upper limit. Specific examples areimpacts generated through an air speed in a range of 1 to 300 m/sec, 1to 250 m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200m/sec or 10 to 150 m/sec.

Here, the speed of the air applied to the freeze-dried composition canbe measured as follows. That is, with the jet type dry powder inhalershown later as Embodiment 1, a mechanism is adopted in which air storedin a bellows body 10 is forcibly introduced onto the freeze-driedcomposition (cake-like freeze-dried composition: hereinafter alsoreferred to as ‘freeze-dried cake’) that has been filled into the vesselfrom an air jet flow path 3, thus applying an air impact, anddischarging the resulting fine particles from a discharge flow path 4.In this case, the flow rate of the air flowing through the air jet flowpath 3 can be calculated by dividing the amount of air stored in thebellows body 10 by the time over which the air is fed into the vessel.Next, by dividing this air flow rate by the cross-sectional area of apath to introduce air into the vessel such as the air jet flow path 3,the air speed at which the impact is applied to the freeze-driedcomposition (freeze-dried cake) can be calculated.Air speed (cm/sec)=air flow rate (ml=cm³/sec)÷cross-sectional area ofair introduction flow path (cm²)

Specifically, in the case for example of a jet type dry powder inhalerdesigned such that the bore of the air jet flow path 3 is 1.2 mm, thebore of the discharge flow path is 1.8 mm, and the amount of air storedin the bellows body 10 is about 20 ml, in the case that the amount ofair of about 20 ml stored in the bellows body 10 is forcibly introducedonto the freeze-dried composition in the vessel from the air jet flowpath 3 in about 0.5 seconds, the air flow rate becomes about 40 ml/sec.Dividing this value by the cross-sectional area of the air introductionflow path (the air jet flow path) (0.06×0.06×3.14=0.0113 cm²), gives3540 cm/sec. The air speed is thus about 35 m/sec.

Moreover, with the self-inhaling type dry powder inhalers shown later asEmbodiments 2, 3 and 4, a mechanism is adopted in which air flowing infrom an air introduction flow path 17 applies an impact to thefreeze-dried cake, and then the resulting fine particles are dischargedfrom a suction flow path 16; the bores of the air introduction flow path17 and the suction flow path 16 thus stipulate the flow rate of the airflowing through the paths. The air speed applied to the freeze-driedcomposition in the vessel can thus be calculated by measuring the flowrate of the air flowing through the air introduction flow path 17 anddividing this by the cross-sectional area of the air introduction flowpath 17.Air speed (cm/sec)=air flow rate (ml=cm³/sec)÷cross-sectional area ofair introduction flow path 17 (cm²)

Specifically, the flow rate of the air flowing through the airintroduction flow path 17 can be measured by installing the dry powderinhaler including the vessel in the slot part of apparatus A (a twinimpinger: made by Copley, UK) as mentioned in the European Pharmacopoeia(Third Edition Supplement 2001, p 113-115), and using a flow meter(KOFLOC DPM-3).

For example, with a self-inhaling type dry powder inhaler designed suchthat the bore of the air introduction flow path 17 is 1.99 mm and thebore of the suction flow path is 1.99 mm, in the case that the air flowrate flowing through the air introduction flow path 17 measured usingthe flow meter (KOFLOC DPM-3) was 17.7 L/min, i.e. 295 ml/sec, the airspeed can be obtained by dividing this value by the cross-sectional areaof the air introduction flow path 17 (0.0995×0.0995×3.14=0.0311 cm²)(9486 cm/sec, i.e. 95 m/sec).

Moreover, at least 17 ml/sec can be given as an example of the flow rateof the air applied to the freeze-dried composition filled in the vessel.The air flow rate is preferably at least 20 ml/sec, more preferably atleast 25 ml/sec. Here there is no particular limitation on the upperlimit of the air flow rate, but an example of 900 L/min can be given.This upper limit is preferably 15 L/sec, more preferably 10 L/sec, yetmore preferably 5 L/sec, still more preferably 4 L/sec, particularlypreferably 3 L/sec. Specifically, the flow rate should be in a rangeconstituted from a lower limit and an upper limit selected asappropriate from the above, with there being no particular limitation;nevertheless, 17 ml/sec to 15 L/sec, 20 ml/sec to 10 L/sec, 20 ml/sec to5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/sec, and 25 ml/sec to 3L/sec, can be given as examples of the range.

Moreover, as means for raising the impact pressure of the air introducedfrom the outside, the dry powder inhaler used in the present inventioncan have means for discharging air from a discharge port, as explainedin detail below, preferably with a small bore, of a flow path close tothe freeze-dried composition housed at the bottom of the vessel, forexample a needle part having an air introduction flow path or an air jetflow path as described later in the embodiments. Regarding the bore ofthe discharge port of the flow path, the preferable range variesaccording to the size of the vessel and so on, with there being noparticular limitations; nevertheless, the bore can be in a range of 0.3to 10 mm, preferably 0.5 to 5 mm, more preferably 0.8 to 5 mm, much morepreferably 1 to 4 mm.

The freeze-dried composition housed in a non-powder form in the vesselcan be made into fine particles by introducing air into the vessel.Here, the extent of making into fine particles should be such that theparticle diameter is suitable for transpulmonary administration; aparticle diameter of 10 μm or less, preferably 5 μm or less, can begiven as an example.

As used herein, the mean particle diameter of fine particles indicates amean particle diameter usually adopted in the industry relating toinhalants. Specifically, the mean particle diameter is not a geometricparticle diameter, but an aerodynamic mean particle diameter (massmedian aerodynamic diameter, MMAD). The aerodynamic mean particlediameter can be measured by a conventional method.

For example, the mass median aerodynamic diameter can be measured usinga dry particle size distribution meter fitted with an Aerobreather,which is an artificial lung model (made by Amherst Process Instrument,Inc., USA), a twin impinger (G. W. Hallworth and D. G. Westmoreland: J.Pharm. Pharmacol., 39, 966-972 (1987), U.S. Pat. No. 6,153,224), amulti-stage liquid impinger, a Marple-Miller impactor, an Andersencascade impactor or the like. Moreover, B. Olsson et al. have reportedthat delivery of the particles into the lungs increases at theproportion of particles having a mass median aerodynamic diameter of 5μm or less increases (B. Olsson et al.: Respiratory Drug Delivery V,273-281 (1996)). The fine particle fraction, fine particle dose or thelike as measured by a twin impinger, a multi-stage liquid impinger, aMarple-Miller impactor, an Andersen cascade impactor or the like acts asa method of estimating the amount that can be delivered into the lungs.In the invention, the proportion of effective particles (fine particlefraction) is at least 10%, preferably at least 20%, more preferably 25%,yet more preferably at least 30%, particularly preferably at least 35%.

The dry powder inhaler for use in the invention encompasses the specificembodiments defined in the following items 100 to 111:

100. A dry powder inhaler for transpulmonary administration used formaking a freeze-dried composition that has been housed in non-powderform in a vessel into fine particles by an air impact, and administeringthe resulting fine particles to a user by inhalation.

101. The dry powder inhaler for transpulmonary administration accordingto item 100, being a device used for making a freeze-dried compositionthat has been housed in non-powder form in a vessel into fine particles,and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding means for feeding airinto the air jet flow path of said needle part, and an inhalation portthat communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding means, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path.

102. The dry powder inhaler for transpulmonary administration accordingto item 100, being a device used for pulverizing a freeze-driedcomposition that has been housed in non-powder form in a vessel intofine particles, and administering the resulting fine particles to a userby inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

103. The dry powder inhaler for transpulmonary administration accordingto item 101, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles anddischarged from said inhalation port through jetting air into saidvessel once.

104. The dry powder inhaler for transpulmonary administration accordingto item 101, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles, such thatthe mean particle diameter is 10 microns or less or the fine particlefraction is 10% or more, and discharged from said inhalation portthrough jetting air into said vessel.

105. The dry powder inhaler for transpulmonary administration accordingto item 101, wherein said air jet flow path and said discharge flow pathare formed in a single needle part.

106. The dry powder inhaler for transpulmonary administration accordingto item 102, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles anddischarged from said inhalation port through one inhalation of the user.

107. The dry powder inhaler for transpulmonary administration accordingto item 102, characterized by being constituted such that saidfreeze-dried composition is pulverized into fine particles, such thatthe mean particle diameter is 10 microns or less or the fine particlefraction is 10% or more, and discharged from said inhalation portthrough inhalation of the user.

108. The dry powder inhaler for transpulmonary administration accordingto item 102, wherein said suction flow path and said air introductionflow path are formed in a single needle part.

109. The dry powder inhaler for transpulmonary administration accordingto item 108 comprising:

a holder part for holding a vessel that is sealed up with a stopper andhouses a freeze-dried composition in a non-powder cake-like form thatwill be made into fine particles upon receiving an air impact,

means for applying an air impact to said freeze-dried composition insaid vessel, and sucking said freeze-dried composition in a powder-formthat has been made into fine particles by the air impact out from saidvessel,

a needle part having a suction flow path for sucking said freeze-driedcomposition out from said vessel, and an air introduction flow path forintroducing outside air into said vessel,

a suction port that communicates with said suction flow path of saidneedle part,

a guide part for guiding said holder part in the axial direction of saidneedle part,

a holder operating part that has a mechanism part for, when said vesselis held by said holder part, advancing the vessel towards a needle tipof said needle part to pierce the stopper of the vessel with said needletip, and retreating the vessel from said needle tip to separate thestopper of the vessel from said needle tip, and an operator thatoperates the mechanism part, and is constituted such that said operatingmember can be operated with a force smaller than the force necessary forthe mechanism part to pierce the stopper of the vessel with said needlepart,

and a housing that supports said needle part and is for providing saidsuction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has beenpierced by said needle part to communicate the suction flow path and theair introduction flow path of said needle part with the inside of saidvessel and position the tip of the air introduction flow path at saidfreeze-dried composition, through the inhalation pressure of a user, airin said vessel is inhaled from said suction port, and air is made toflow into said vessel through the air introduction flow path, thusapplying an air impact to the freeze-dried composition in said vessel.

110. The dry powder inhaler for transpulmonary administration accordingto item 109, characterized in that said housing is formed in a tubularshape, said suction port is formed at a tip part of the housing, ahousing chamber for housing said vessel via said holder is formed insaid housing, said needle part is disposed in said housing such thatsaid needle tip points towards said housing chamber, and an introductionport for introducing outside air that communicates with the airintroduction flow path of said needle part is provided in a wall of saidhousing,

and the dry powder inhaler is constituted such that said holder part isadvanced and retreated in the axial direction of said housing in saidhousing chamber using said holder operating part.

111. The dry powder inhaler for transpulmonary administration accordingto item 110, characterized in that said housing is formed from a housingmain body having a removal/insertion port for said vessel formed thereinin a position in which said holder part is retreated, and a lid for saidremoval/insertion port that is connected to said housing main body by ahinge,

and the dry powder inhaler is constituted such that said holderoperating part has said mechanism part which advances said holder parttowards the needle tip of the needle part when said lid is pushed downto close said removal/insertion port, and retreats said holder part awayfrom said needle tip when said lid is lifted up to open saidremoval/insertion port, and said lid is used as the operating member ofsaid mechanism part.

(2) Freeze-Dried Composition

The freeze-dried composition of the present invention is a compositionthat is prepared in a non-powder dry form by filling solution containinga single effective dose or a plurality of effective doses of a drug intoa vessel and then freeze-drying as is. It is preferably a freeze-driedcomposition containing a single effective dose of the drug. Thenon-powder-form freeze-dried composition can be manufactured by the samemethod as a conventional manufacturing method used for a freeze-driedpreparation (freeze-dried composition) such as an injection that isdissolved at the time of use, in which a liquid is filled in subdividedamounts into vessels; by selecting a suitable composition (types andamounts of active ingredient and carrier used together with the activeingredient) such that the disintegration index of the freeze-driedcomposition prepared is 0.015 or more, the freeze-dried composition canbe made into fine particles down to a particle diameter suitable fortranspulmonary administration in an instant by receiving an impact ofexternal air (air impact, jet pressure) introduced into (flowing into)the vessel.

Note that the disintegration index in the present invention is a valuecharacteristic of the freeze-dried composition that can be obtained bymeasuring following the undermentioned method.

<Disintegration Index>

0.2 to 0.5 ml of a mixture containing target components that willconstitute the freeze-dried composition is filled into a vessel having atrunk diameter of 18 mm or 23 mm, and freeze-drying is carried out.Next, 1.0 ml of n-hexane is instilled gently down the wall of the vesselonto the non-powder-form freeze-dried composition obtained. Agitation iscarried out for about 10 seconds at 3000 rpm, and then the mixture isput into a UV cell of optical path length 1 mm and optical path width 10mm, and the turbidity is measured immediately at a measurementwavelength of 500 nm using a spectrophotometer. The turbidity obtainedis divided by the total amount (weight)) of the components constitutingthe freeze-dried composition, and the value obtained is defined as thedisintegration index.

Here, an example of the lower limit of the disintegration index of thefreeze-dried composition of the invention can be given as theabove-mentioned 0.015, preferably 0.02, more preferably 0.03, yet morepreferably 0.04, still more preferably 0.05. Especially, 0.1 ispreferable. Moreover, there is no particular limitation on the upperlimit of the disintegration index of the freeze-dried composition of theinvention, but an example can be given as 1.5, preferably 1, morepreferably 0.9, yet more preferably 0.8, still more preferably 0.7. Thefreeze-dried composition of the present invention preferably has adisintegration index in a range constituted from a lower limit and anupper limit selected as appropriate from the above, with the provisothat the disintegration index is at least 0.015. Specific examples ofthe range of the disintegration index are 0.015 to 1.5, 0.02 to 1.0,0.03 to 0.9, 0.04 to 0.8, 0.05 to 0.7 and 0.1 to 0.7.

Moreover, it is preferable to prepare the freeze-dried composition ofthe present invention in a non-powder cake-like form by freeze-drying.In the present invention, ‘non-powder-form freeze-dried composition’means a dry solid obtained by freeze-drying a solution, and is generallycalled a ‘freeze-dried cake’. However, even if cracks appear in thecake, the cake breaks into a plurality of large lumps, or part of thecake breaks into a powder during the freeze-drying process or duringsubsequent handling, this cake is still included as a non-powder-formfreeze-dried composition that is the subject of the present invention,provided the effects of the present invention are not impaired.

As described above, the freeze-dried composition of the invention has adisintegration index of 0.015 or more and a non-powder cake-like formand becomes fine particles having a mean particle diameter of 10 micronsor less or a fine particle fraction of 10% or more upon receipt of anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec.

A preferable freeze-dried composition is such that, upon receiving theabove air impact, the mean particle diameter becomes 10 microns or lessand preferably 5 microns or less or a fine particle fraction of 10% ormore, preferably 20% or more, more preferably 25% or more, still morepreferably 30% or more, and especially more preferably 35% or more.

As described above, the air impact applied to a freeze-dried compositionis not limited, as long as it is generated by air having an air speed ofat least 1 m/sec and an air flow rate of at least 17 ml/sec.

Specific examples of an air impact include an impact generated by an airhaving a speed of 1 m/sec or more, preferably 2 m/sec or more, morepreferably 5 m/sec or more and a still more preferably 10 m/sec or more.Here, there is no limitation on the upper limit of the air speed, but itis generally 300 m/sec, preferably 250 m/sec, more preferably 200 m/secand yet more preferably 150 m/sec. The air speed is not limited as longas it is arbitrary selected from the range extending from a lower limitto an upper limit; however, the ranges of 1 to 300 m/sec, 1 to 250m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200 m/secor 10 to 150 m/sec can be given as examples.

Examples of the air impact include those generated by air having an airflow rate of generally 17 ml/sec or more, preferably 20 ml/sec or moreand more preferably 25 ml/sec or more. There is no limitation on theupper limit of the air flow rate; however, the air flow rate isgenerally 900 L/min, preferably 15 L/sec, more preferably 5 L/sec yetmore preferably 4 L/sec. Especially, 3 L/sec is very preferable. Morespecifically, the air flow rate is not limited as long as it is selectedfrom the range extending from a lower limit to an upper limit; however,examples of such a range include 17 ml/sec to 15 L/sec, 20 ml/sec to 10L/sec, 20 ml/sec to 5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/secand 25 ml/sec to 3 L/sec.

In principle, there is no particular limitation on the drug used in thepresent invention, provided it is a drug that can be used as a powderedinhalation (powdered inhalation for transpulmonary administration);nevertheless, synthetic low-molecular-weight drugs andhigh-molecular-weight drugs can be given as specific examples.High-molecular-weight drugs include physiologically active substancessuch as proteins, peptides or polypeptides, antibodies, genes, nucleicacids, enzymes, hormones and the like.

Moreover, regarding the disease targeted by the drug, both whole bodytreatment and local treatment can be envisaged, depending on the case.

Examples of synthetic low-molecular-weight drugs include, for example,hydrocortisone, prednisolone, triamcinolone, dexamethasone,betamethasone, beclometasone, fluticasone, mometasone, budesonide,salbutamol, salmeterol, procaterol, buprenorphine hydrochloride,apomorphine, taxol, and antibiotics such as tobramycin.

Examples of bio-drugs (physiologically active substances) such asproteins, peptides or polypeptides, antibodies, genes, nucleic acids,enzymes and hormones include, for example, interferons (α, β, γ),interleukins (for example, interleukin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18 etc.), anti-interleukin-1α antibody,interleukin-1 receptor, interleukin receptor antagonist, interleukin-4receptor, anti-interleukin-2 antibody, anti-interleukin-6 receptorantibody, interleukin-4 antagonist, interleukin-6 antagonist,anti-interleukin-8 antibody, chemokine receptor antagonist,anti-interleukin-7 receptor, anti-interleukin-7 antibody,anti-interleukin-5 antibody, interleukin-5 receptor, anti-interleukin-9antibody, interleukin-9 receptor, anti-interleukin-10 antibody,interleukin-10 receptor, anti-interleukin-14 antibody, interleukin-14receptor, anti-interleukin-15 antibody, interleukin-15 receptor,interleukin-18 receptor, anti-interleukin-18 antibody, erithropoietin(EPO), erithropoietin derivatives, granulocyte colony stimulating factor(G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF),macrophage colony stimulating factor (M-CSF), calcitonin, insulin,insulin derivatives (LisPro, NovoRapid, HOE901, NN-304, etc.),insulintropin, insulin-like growth factor, glucagon, somatostatin andanalogs thereof, vasopressin and analogs thereof, amylin, human growthhormone, luteinizing hormone releasing hormone, follicle stimulatinghormone, growth hormone releasing factor, parathyroid hormone,endothelial cell growth factor, platelet derived growth factor,keratinocyte growth factor, epidermal growth factor, fibroblast growthfactor, brain-derived neurotrophic factor, ciliary neurotrophic factor,tumor necrosis factor (TNF), TNF receptor, TNF inhibitor, transforminggrowth factor (TGF), hepatocyte growth factor (HGF), nerve growth factor(NGF), blood stem cell growth factor, platelet growth simulator,naturiuretic peptide, blood coagulation factor, blood hepatocyte growthfactor (S-CSF), FLT3 ligand, anti-platelet aggregation inhibitingmonoclonal antibody, tissue plasminogen activator and derivativesthereof, superoxide dismutase, antisense drugs, immunosuppression agents(for example, cyclosporin, tacrolimus hydrate, etc.) cancer repressorgene p53, cystic fibrosis transmembrane conductance regulator (CFTR)gene, α-1 antitrypsin, thrombopoietin (TPO), metastatin,deoxyribonuclease (Dnase), prolactin, oxytocin, thyrotopin releasinghormone (TRH), bactericidal permeability increasing (BPI) protein, andvaccine preparations, for example influenza vaccines, AIDS vaccines,rotavirus vaccines, malaria vaccines and tuberculosis vaccines such asMtb72f.

One of these active ingredients can be used alone, or two or more can beused in combination. Note that the various peptides above encompassnatural polypeptides, gene recombinant polypeptides, chemicallysynthesized polypeptides and so on.

The freeze-dried composition of the present invention may comprise theactive ingredient alone, as long as the end products satisfy theabove-mentioned disintegration index, or a suitable carrier may be mixedin. In the case of using a carrier in addition to the active ingredient,there are no particular limitations on the type and amount of thecarrier used, so long as the final freeze-dried composition prepared bymixing with the active ingredient satisfies the above-mentioneddisintegration index, and the effects of the present invention (makinginto a fine particle) attained.

Specific examples of the carrier include hydrophobic amino acids such asvaline, leucine, isoleucine and phenylalanine, and salts and amidesthereof; hydrophilic amino acids such as glycine, proline, alanine,arginine and glutamic acid, and salts and amides thereof; derivatives ofamino acids; and dipeptides, tripeptides or the like having two or moreof the same one or different ones of the above-mentioned amino acids,and salts and amides thereof. One of these can be used alone, or two ormore can be used in combination. Here, examples of salts of the aminoacid or peptide include salts with an alkali metal such as sodium orpotassium or an alkaline earth metal such as calcium, and addition saltswith an inorganic acid such as phosphoric acid or hydrochloric acid oran organic acid such as sulfonic acid, while examples of amides includeL-leucine amide hydrochloride.

Moreover, an amino acid other than an α-amino acid can be used in as acarrier. Examples of such an amino acid include β-alanine,γ-aminobutyric acid, homoserine and taurine. Other examples of carriersinclude monosaccharides such as glucose; disaccharides such assaccharose, maltose, lactose and trehalose; sugar alcohols such asmannitol; oligosaccharides such as cyclodextrin; polysaccharides such asdextran 40 and pullulan; polyhydric alcohols such as polyethyleneglycol; and fatty acid sodium salts such as sodium caprate. One of thesecarriers may be used alone, or two or more may be used in combination.

Of the above carriers, specific examples of carriers that are preferablefor delivering the active ingredient efficiently into the lungs includehydrophobic amino acids such as isoleucine, valine, leucine andphenylalanine, and salts and amides thereof; hydrophobic dipeptides suchas leucyl-valine, leucyl-phenylalanine and phenylalanyl-isoleucine; andhydrophobic tripeptides such as leucyl-leucyl-leucine andleucyl-leucyl-valine. Again, one of these may be used alone, or two ormore may be used in combination.

There are no particular limitations on the proportion of the activeingredient(s) (drug(s)) mixed into the freeze-dried composition;nevertheless, examples of the content are 20 mg or less, preferably 10mg or less, more preferably 5 mg or less, yet more preferably 2 mg orless, particularly preferably 1 mg or less.

Moreover, there are no particular limitations on the mixing proportionof the carrier(s), provided the final freeze-dried composition satisfiesthe above-mentioned disintegration index; nevertheless, as a guideline,per 100 wt % of the freeze-dried composition, the range is generallyfrom 0.1 to less than 100 wt %, preferably from 1 to less than 100 wt %,more preferably from 10 to less than 100 wt %, particularly preferablyfrom 20 to less than 100 wt %.

Note that, in addition to the above-mentioned components, thefreeze-dried composition that is the subject of the present inventionmay have mixed therein various additives, for example for stabilizingthe active ingredient(s) in solution before drying, for stabilizing theactive ingredient(s) after drying, or for preventing the activeingredient(s) from sticking to the vessel, provided that theabove-mentioned disintegration index is satisfied and the effects of thepresent invention are not impaired. For example, the freeze-driedcomposition may contain human serum albumin, inorganic salts,surfactants, buffering agents and so on. A wide range of surfactants canbe used, regardless of whether they are anionic surfactants, cationicsurfactants or nonionic surfactants, provided that they are surfactantsthat are generally used in medicines. Preferable examples are nonionicsurfactants such as sorbitan trioleate and polyoxyethylene sorbitanfatty acid esters (for example Tween type surfactants).

The freeze-dried composition for use in the invention encompasses thespecific embodiments defined in the following items 201 to 220:

201. A freeze-dried composition for transpulmonary administration havingthe following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.015 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof an air impact having an air speed of at least 1 m/sec and an air flowrate of at least 17 ml/sec.

202. The freeze-dried composition according to item 201, wherein thedisintegration index is 0.02 or more.

203. The freeze-dried composition according to item 201, wherein thedisintegration index is 0.015 to 1.5.

204. The freeze-dried composition according to item 201, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receipt of an air impacthaving an air speed of at least 2 m/sec and an air flow rate of at least17 ml/sec.

205. The freeze-dried composition according to item 201, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receiving an air impacthaving an air speed in a range of 1 to 300 m/sec and an air flow rate ofat least 17 ml/sec.

206. The freeze-dried composition according to item 201, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receipt of an air impacthaving an air speed of at least 1 m/sec and an air flow rate of at least20 ml/sec.

207. The freeze-dried composition according to item 201, becoming fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more upon receiving an air impacthaving an air speed of at least 1 m/sec and an air flow rate in a rangeof 17 ml/sec to 15 L/sec.

208. The freeze-dried composition according to item 201, becoming fineparticles having a mean particle diameter of 5 microns or less or a fineparticle fraction of 20% or more upon receiving an air impact.

209. The freeze-dried composition according to item 201, containing asynthetic low-molecular-weight drug as an active ingredient.

210. The freeze-dried composition according to item 201, containing ahigh-molecular-weight drug such as a protein, a peptide or the like asan active ingredient.

211. The freeze-dried composition according to item 209, containing asynthetic low-molecular-weight drug as the active ingredient, and atleast one selected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

212. The freeze-dried composition according to item 210, containing ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

213. The freeze-dried composition according to item 211, containing asynthetic low-molecular-weight drug as the active ingredient, and atleast one selected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

214. The freeze-dried composition according to item 212, characterizedby containing a high-molecular-weight drug such as a protein, a peptideor the like as the active ingredient, and at least one selected from thegroup consisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

215. The freeze-dried composition according to item 201, being awater-soluble composition.

216. The freeze-dried composition according to item 201, containing asingle dose of an active ingredient.

217. The freeze-dried composition according to item 201, being afreeze-dried composition for transpulmonary administration having thefollowing properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index in a range of 0.015 to 1.5, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receiving an air impact having an air speed in a range of 1        to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15        L/sec.

218. The freeze-dried composition according to item 217, wherein thedisintegration index is 0.02 to 1.0.

219. The freeze-dried composition according to item 217, wherein the airspeed is 1 to 250 m/sec.

220. The freeze-dried composition according to item 217, wherein the airflowrate is 20 ml/sec to 10 L/sec.

(3) Dry Powder Inhalation System for Transpulmonary Administration

The dry powder inhalation system for transpulmonary administration ofthe present invention is a system that combines a freeze-driedcomposition having a composition such that, by applying an air impact tothe freeze-dried composition which exists in a non-powder form havingbeen freeze-dried in a vessel and not subjected to processing such aspulverization, the freeze-dried composition can be made into fineparticles having a mean particle diameter of 10 microns or less or afine particle fraction of 10% or more in the vessel, and a inhalingdevice comprising prescribed means. According to this dry powderinhalation system for transpulmonary administration, a user him/herselfcan prepare the freeze-dried composition which has been provided in anon-powder form into a powdered preparation comprising fine particleshaving a mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more, which is a preparation suitable fortranspulmonary administration, at the time of use (the time ofinhalation), and administer (take) the powdered preparation.

To obtain the effects of the dry powder inhalation system fortranspulmonary administration effectively, it is important to select thecomposition of the freeze-dried composition, the inhaling device, thevessel and so on appropriately. As the inhaling device, it is preferableto adopt a device comprising {circle around (1)} means for applying anair impact (or means for introducing air) and {circle around (2)} meansfor discharging fine particles (or means for administering byinhalation), in which, by means for introducing air (means {circlearound (1)}) air is introduced into (inflow) a vessel which houses thenon-powder-form freeze-dried composition and the freeze-driedcomposition is pulverized into fine particles using the impact (jetpressure) of the air that has been introduced into (flowed into) thevessel, and then, using the means {circle around (2)} for dischargingfine particles, the dried powder composition made into fine particles bymeans {circle around (1)} is discharged from the vessel. Then, the fineparticles are directly administered to a user.

An example of such device is the dry powder inhaler of the inventionmentioned earlier. Moreover, the freeze-dried composition mentionedearlier is a suitable example of a freeze-dried composition that caneasily be made into fine particles through an air impact (jet pressure)of external air introduced into (flowing into) the vessel by the meansfor applying an air impact (means for introducing air) of theabove-mentioned device.

The dry powder inhalation system suitable for transpulmonaryadministration according to the invention includes a vessel housing thefreeze-dried composition of the invention and a dry powder inhaler ofthe invention used in combination at the time of inhalation. In otherwords, the dry powder inhalation system of the invention, at least whenused for inhalation, comprises the vessel housing the freeze-driedcomposition of the invention and the dry powder inhaler of theinvention.

According to the system of the invention, by introducing air into thevessel using the dry powder inhaler for applying an air impact having anair speed of at least 1 m/sec and an air flow rate of at least 17 ml/secto the freeze-dried composition in the vessel, a dry powderedpreparation having a particle size suitable for transpulmonaryadministration can be obtained. Furthermore, the system allowstranspulmonary administration of the obtained dry powdered preparationdirectly to a user by inhalation. Therefore, the dry powder inhalationsystem for transpulmonary administration of the invention is a systemfor producing a dry powdered preparation suitable for transpulmonaryadministration and, at the same time, a system for transpulmonarilyadministering the dry powder preparation to a user.

The dry powder inhalation system for transpulmonary administration ofthe invention encompasses the specific embodiments defined in thefollowing items 301 to 322:

301. A dry powder inhalation system for transpulmonary administration,using a combination of:

(1) a vessel housing a freeze-dried composition that contains a singledose of an active ingredient, and has:

-   -   (i) a non-powder cake-like form,    -   (ii) a disintegration index of 0.015 or more, and    -   (iii) a property of becoming fine particles having a mean        particle diameter of 10 microns or less or a fine particle        fraction of 10% or more upon receiving an air impact having an        air speed of at least 1 m/sec and an air flow rate of at least        17 ml/sec; and

(2) a device comprising means capable of applying said air impact to thefreeze-dried composition in said vessel, and means for discharging thepowder-form freeze-dried composition that has been made into fineparticles.

302. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the vessel and the device are used incombination at the time of inhalation.

303. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the disintegration index of thefreeze-dried composition is 0.02 or more.

304. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the disintegration index of thefreeze-dried composition is in a range of 0.015 to 1.5.

305. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the air impact of (iii) is generated byair having an air speed of at least 2 m/sec and an air flow rate of atleast 17 ml/sec.

306. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the air impact of (iii) is generated byair having an air speed in a range of 1 to 300 m/sec and an air flowrate of at least 17 ml/sec.

307. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the air impact of (iii) is generated byair having an air speed of at least 1 m/sec and an air flow rate of atleast 20 ml/sec.

308. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the air impact of (iii) is generated byair having an air speed of at least 1 m/sec and an air flow rate in arange of 17 ml/sec to 15 L/sec.

309. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the freeze-dried composition has aproperty of becoming fine particles having a mean particle diameter of 5microns or less or a fine particle fraction of 20% or more upon receiptof an air impact.

310. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the freeze-dried composition contains asynthetic low-molecular-weight drug as the active ingredient.

311. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient.

312. The dry powder inhalation system for transpulmonary administrationaccording to item 310, wherein the freeze-dried composition contains asynthetic low-molecular-weight drug as the active ingredient, and atleast one selected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

313. The dry powder inhalation system for transpulmonary administrationaccording to item 311, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

314. The dry powder inhalation system for transpulmonary administrationaccording to item 312, wherein the freeze-dried composition contains asynthetic low-molecular-weight drug as the active ingredient, and atleast one selected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

315. The dry powder inhalation system for transpulmonary administrationaccording to item 313, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient, and at least one selected from the groupconsisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

316. The dry powder inhalation system for transpulmonary administrationaccording to item 301, wherein the freeze-dried composition is awater-soluble composition.

317. The dry powder inhalation system for transpulmonaty administrationaccording to item 301, wherein the device is:

i) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle parthaving a discharge flow path, air pressure-feeding means for feeding airinto the air jet flow path of said needle part, and an inhalation portthat communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals upsaid vessel is pierced by said needle parts, thus communicating the airjet flow path and the discharge flow path with the inside of saidvessel, and air is jetted into said vessel through said air jet flowpath using said air pressure-feeding means, thus pulverizing saidfreeze-dried composition into fine particles by the impact of the jettedair, and discharging the fine particles obtained from the inhalationport via said discharge flow path, or

ii) a dry powder inhaler for transpulmonary administration, being adevice used for making a freeze-dried composition that has been housedin non-powder form in a vessel into fine particles, and administeringthe resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle parthaving an air introduction flow path, and an inhalation port thatcommunicates with said suction flow path,

and characterized by being constituted such that, in a state in which astopper sealing up said vessel has been pierced by said needle parts,through the inhalation pressure of the user, air in said vessel isinhaled from said inhalation port, and at the same time outside airflows into said vessel, at a negative pressure, through said airintroduction flow path, and as a result said freeze-dried composition ispulverized into fine particles by the impact of the air flowing in, andthe fine particles obtained are discharged from the inhalation portthrough said suction flow path.

318. The dry powder inhalation system for transpulmonary administrationaccording to item 317, as the device, using the dry powder inhalercomprising:

a holder part for holding a vessel that is sealed up with a stopper andhouses a freeze-dried composition in a non-powder cake-like form thatwill be made into fine particles upon receiving an air impact,

means for applying an air impact to said freeze-dried composition insaid vessel, and sucking said freeze-dried composition in a powder-formthat has been made into fine particles by the air impact out from saidvessel,

a needle part having a suction flow path for sucking said freeze-driedcomposition out from said vessel, and an air introduction flow path forintroducing outside air into said vessel,

a suction port that communicates with said suction flow path of saidneedle part,

a guide part for guiding said holder part in the axial direction of saidneedle part,

a holder operating part that has a mechanism part for, when said vesselis held by said holder part, advancing the vessel towards a needle tipof said needle part to pierce the stopper of the vessel with said needletip, and retreating the vessel from said needle tip to separate thestopper of the vessel from said needle tip, and an operator thatoperates the mechanism part, and is constituted such that said operatingmember can be operated with a force smaller than the force necessary forthe mechanism part to pierce the stopper of the vessel with said needlepart,

and a housing that supports said needle part and is for providing saidsuction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has beenpierced by said needle part to communicate the suction flow path and theair introduction flow path of said needle part with the inside of saidvessel and position the tip of the air introduction flow path at saidfreeze-dried composition, through the inhalation pressure of a user, airin said vessel is inhaled from said suction port, and air is made toflow into said vessel through the air introduction flow path, thusapplying an air impact to the freeze-dried composition in said vessel.

319. The dry powder inhalation system for transpulmonary administrationaccording to item 301, using a combination of:

(1) a vessel housing a freeze-dried composition that contains a singledose of an active ingredient, and has:

-   -   (i) a non-powder cake-like form,    -   (ii) a disintegration index in a range of 0.015 to 1.5, and    -   (iii) a property of becoming fine particles having a mean        particle diameter of 10 microns or less or a fine particle        fraction of 10% or more upon receipt of an air impact having an        air speed in a range of 1 to 300 m/sec and an air flow rate in a        range of 17 ml/sec to 15 L/sec; and

(2) a device comprising means capable of applying said air impact to thefreeze-dried composition in said vessel, and means for discharging thepowder-form freeze-dried composition that has been made into fineparticles.

320. The dry powder inhalation system for transpulmonary administrationaccording to item 319, wherein the disintegration index is 0.02 to 1.0.

321. The dry powder inhalation system for transpulmonary administrationaccording to item 319, wherein the air speed is 1 to 250 m/sec.

322. The dry powder inhalation system for transpulmonary administrationaccording to item 319, wherein the air flow rate is 20 ml/sec to 10L/sec.

(4) Method of Manufacturing a Dry Powdered Preparation

Moreover, the present invention relates to a method of manufacturing adry powdered preparation comprising fine particles with a particlediameter suitable for transpulmonary administration (dry powderedpreparation for transpulmonary administration) by inhalation, by makinga freeze-dried composition that has been housed in a non-powder form ina vessel into fine particles. The manufacturing method can beimplemented in the vessel housing the non-powder form freeze-driedcomposition by applying a predetermined air impact. Specifically, themethod of manufacturing the dry powder preparation of the invention canbe carried out by applying an air impact having an air speed of at least1 m/sec and an air flow rate of at least 17 ml/sec to theabove-mentioned non-powder form freeze-dried composition of theinvention. Thereby, the non-powder form freeze-dried composition can bemade into a dry powdered preparation having a mean particle diameter of10 microns or less, preferably 5 microns or less or a fine particlefraction of 10% or more, preferably 20% or more, more preferably 25% ormore, and still more preferably 30% or more. The method of applying theair impact to the freeze-dried composition is, not limited; however, theabove-mentioned dry powder inhaler of the invention is preferably used.

It is preferable that the manufacturing method be implemented byintroducing air capable of applying the above-described air impact to afreeze-dried composition into the vessel housing a non-powderfreeze-dried composition. The method of manufacturing the dry powderedpreparation of the invention is characterized in that a patientadministering the dry powdered preparation can prepare by him/herselfthe powdered preparation at the time of use (inhalation) by making thefreeze-dried composition housed in a vessel into fine particles having aparticle diameter suitable for transpulmonary administration.

The method of manufacturing a dry powdered preparation of the inventionencompasses the specific embodiments defined in the following items 401to 424:

401. A method of manufacturing a dry powdered preparation fortranspulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed of at least 1 m/sec and an air flow rateof at least 17 ml/sec using a device capable of applying said air impactto the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more;

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of the air impact.

402. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein the fineparticles prepared have a mean particle diameter of 5 microns or less ora fine particle fraction of 20% or more.

403. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein thedisintegration index of the freeze-dried composition is 0.02 or more.

404. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein thedisintegration index of the freeze-dried composition is in a range of0.015 to 1.5.

405. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein thefreeze-dried composition contains a synthetic low-molecular-weight drugas the active ingredient.

406. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein thefreeze-dried composition contains a high-molecular-weight drug such as aprotein, a peptide or the like as the active ingredient.

407. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 405, wherein thefreeze-dried composition contains a synthetic low-molecular-weight drugas the active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

408. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 406, wherein thefreeze-dried composition contains a high-molecular-weight drug such as aprotein, a peptide or the like as the active ingredient, and at leastone selected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

409. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 407, wherein thefreeze-dried composition contains a synthetic low-molecular-weight drugas the active ingredient, and at least one selected from the groupconsisting of hydrophobic amino acids, hydrophobic dipeptides, andhydrophobic tripeptides as the carrier.

410. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 408, wherein thefreeze-dried composition contains a high-molecular-weight drug such as aprotein, a peptide or the like as the active ingredient, and at leastone selected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

411. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, wherein thefreeze-dried composition is a water-soluble composition.

412. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, being a method ofmaking the freeze-dried composition into fine particles in a vesselhaving a volume of 0.2 to 50 ml.

413. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, carried out byusing a device having means capable of applying an air impact having anair speed of at least 2 m/sec and an air flow rate of at least 17 ml/secto the freeze-dried composition in the vessel, and introducing airhaving the air impact into the vessel housing the freeze-driedcomposition.

414. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, carried out byusing a device having means capable of applying an air impact having anair speed in a range of 1 to 300 m/sec and an air flow rate of at least17 ml/sec to the freeze-dried composition in the vessel, and introducingair having the air impact into the vessel housing the freeze-driedcomposition.

415. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, carried out byusing a device having means capable of applying an air impact having anair speed of at least 1 m/sec and an air flow rate of at least 20 ml/secto the freeze-dried composition in the vessel, and introducing airhaving the air impact into the vessel housing the freeze-driedcomposition.

416. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, carried out byusing a device having means capable of applying an air impact having anair speed of at least 1 m/sec and an air flow rate in a range of 17ml/sec to 15 L/sec to the freeze-dried composition in the vessel, andintroducing air having the air impact into the vessel housing thefreeze-dried composition.

417. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, characterized bymaking the freeze-dried composition into fine particles using the drypowder inhaler of item 101 or 102 shown in the section of (1) Dry powderinhaler as the device.

418. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 417, characterized bymaking the freeze-dried composition into fine particles using the drypowder inhaler according to item 109 shown in the section of (1) Drypowder inhaler as the device.

419. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 417, being a method ofmanufacturing a dry powdered preparation in which the freeze-driedcomposition is made into fine particles using the dry powder inhaleraccording to item 101 shown in the section of (1) Dry powder inhaler,wherein the amount of air jetted into said vessel each time using thedry powder inhaler is 5 to 100 ml.

420. The method of manufacturing a powdered preparation fortranspulmonary administration according to item 417, being a method ofmanufacturing a dry powdered preparation in which the freeze-driedcomposition is made into fine particles using the dry powder inhaler ofitem 102 shown in the section of (1) Dry powder inhaler, wherein theflow rate of air inhalation from the inhalation port using the drypowder inhaler is 5 to 300 L/min.

421. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 401, comprising:

introducing air into a vessel to apply to a freeze-dried composition anair impact having an air speed in a range of 1 to 300 m/sec and an airflow rate in a range of 17 ml/sec to 15 L/sec using a device capable ofapplying said air impact to the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more;

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index in a range of 0.015 to 1.5, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of the air impact.

422. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 421, wherein thedisintegration index is 0.02 to 1.0.

423. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 421, wherein the airspeed is 1 to 250 m/sec.

424. The method of manufacturing a dry powdered preparation fortranspulmonary administration according to item 421, wherein the airflow rate is 20 ml/sec to 10 L/sec.

(5) Transpulmonary Administration Method

The present invention further provides a transpulmonary administrationmethod comprising making a freeze-dried composition in a non-powder forminto fine particles suitable for transpulmonary administration at thetime of usage (administration), and administering the resultingpreparation in a powder form with fine particles by inhalation. Thetranspulmonary administration method can be carried out using theabove-described dry powder inhalation system for transpulmonaryadministration of the invention comprising the vessel housing thefreeze-dried composition of the invention and the dry powder inhaler ofthe invention.

The transpulmonary administration method of the invention encompassesthe specific embodiments defined in the following items 501 to 522:

501. A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a meanparticle diameter of 10 microns or less or a fine particle fraction of10% or more by applying an air impact having an air speed of at least 1m/sec and an air flow rate of at least 17 ml/sec to the freeze-driedcomposition at the time of use, and

administering the resulting fine particle powder to a user byinhalation;

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.015 or more, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more upon receiptof the air impact.

502. The transpulmonary administration method according to item 501,wherein the freeze-dried composition is housed in a vessel, and the fineparticle powder are made using a device comprising means capable ofapplying the air impact to the freeze-dried composition in the vesseland means for discharging the resulting fine particle powder-formfreeze-dried composition out of the vessel.

503. The transpulmonary administration method according to item 502,wherein the disintegration index of the freeze-dried composition is 0.02or more.

504. The transpulmonary administration method according to item 502,wherein the disintegration index of the freeze-dried composition is in arange of 0.015 to 1.5.

505. The transpulmonary administration method according to item 502,wherein the air impact of (iii) is generated by air having an air speedof at least 2 m/sec and an air flow rate of at least 17 ml/sec.

506. The transpulmonary administration method according to item 502,wherein the air impact of (iii) is generated by air having an air speedin a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

507. The transpulmonary administration method according to item 502,wherein the air impact of (iii) is generated by air having an air speedof at least 1 m/sec and an air flow rate of at least 20 ml/sec.

508. The transpulmonary administration method according to item 502,wherein the air impact of (iii) is generated by air having an air speedof at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15L/sec.

509. The transpulmonary administration method according to item 502,wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as the active ingredient.

510. The transpulmonary administration method according to item 502,wherein the freeze-dried composition contains a high-molecular-weightdrug such as a protein, a peptide or the like as the active ingredient.

511. The transpulmonary administration method according to item 509,wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

512. The transpulmonary administration method according to item 510,wherein the freeze-dried composition contains a high-molecular-weightdrug such as a protein, a peptide or the like as the active ingredient,and at least one selected from the group consisting of amino acids,dipeptides, tripeptides, and saccharides as a carrier.

513. The transpulmonary administration method according to item 511,wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

514. The transpulmonary administration method according to item 512,wherein the freeze-dried composition contains a high-molecular-weightdrug such as a protein, a peptide or the like as the active ingredient,and at least one selected from the group consisting of hydrophobic aminoacids, hydrophobic dipeptides, and hydrophobic tripeptides as thecarrier.

515. The transpulmonary administration method according to item 502,wherein the freeze-dried composition is a water-soluble composition.

516. The transpulmonary administration method according to item 502,being a method of making into fine particles and administering such thatthe fine particles have a mean particle diameter of 5 microns or less ora fine particle fraction of 20% or more.

517. The transpulmonary administration method according to item 502,using the dry powder inhaler of item 101 or 102 shown in the section of(1) Dry powder inhaler as the device.

518. The transpulmonary administration method according to item 517,using the dry powder inhaler of item 109 shown in the section of (1) Drypowder inhaler as the device.

519. The transpulmonary administration method according to item 502,wherein the freeze-dried composition has the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index in a range of 0.015 to 1.5, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receiving an air impact having an air speed in a range of 1        to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15        L/sec,        and the fine particles are made using a dry powder inhaler        comprising means capable of applying said air impact to the        freeze-dried composition in the vessel and means for discharging        the resulting fine particle powder-form freeze-dried composition        out of the vessel.

520. The transpulmonary administration method according to item 519,wherein the disintegration index is 0.02 to 1.0.

521. The transpulmonary administration method according to item 519,wherein the air speed is 1 to 250 m/sec.

522. The transpulmonary administration method according to item 519,wherein the air flow rate is 20 ml/sec to 10 L/sec.

(6) Use of a Freeze-Dried Composition for Transpulmonary Administrationby Inhalation

The present invention also provides use of a freeze-dried composition ina non-powder form for the transpulmonary administration by inhalation.The use encompasses the specific embodiments defined in the followingitems 601 to 622:

601. Use of a freeze-dried composition for transpulmonary administrationby inhalation,

the freeze-dried composition containing a single dose of an activeingredient and having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of an air impact having an air speed of at least 1        m/sec and an air flow rate of at least 17 ml/sec,        and being used by forming into fine particles having said mean        particle diameter or said fine particle fraction.

602. The use of a freeze-dried composition for transpulmonaryadministration according to item 601, wherein the freeze-driedcomposition is housed in a vessel, and the fine particles are made usinga device comprising means capable of applying the air impact to thefreeze-dried composition in the vessel and means for discharging theresulting fine particle powder-form freeze-dried composition out of thevessel.

603. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the disintegration indexof the freeze-dried composition is 0.02 or more.

604. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the disintegration indexof the freeze-dried composition is in a range of 0.015 to 1.5.

605. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 2 m/sec and anair flow rate of at least 17 ml/sec.

606. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate of at least 17 ml/sec.

607. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 1 m/sec and anair flow rate of at least 20 ml/sec.

608. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed of at least 1 m/sec and anair flow rate in a range of 17 ml/sec to 15 L/sec.

609. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition becomes fine particles having a mean particle diameter of 5microns or less or a fine particle fraction of 20% or more uponreceiving an air impact.

610. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition contains a synthetic low-molecular-weight drug as the activeingredient.

611. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as a protein, apeptide or the like as the active ingredient.

612. The use of a freeze-dried composition for transpulmonaryadministration according to item 610, wherein the freeze-driedcomposition contains a synthetic low-molecular-weight drug as the activeingredient, and at least one selected from the group consisting of aminoacids, dipeptides, tripeptides, and saccharides as a carrier.

613. The use of a freeze-dried composition for transpulmonaryadministration according to item 611, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as a protein, apeptide or the like as the active ingredient, and at least one selectedfrom the group consisting of amino acids, dipeptides, tripeptides, andsaccharides as a carrier.

614. The use of a freeze-dried composition for transpulmonaryadministration according to item 612, wherein the freeze-driedcomposition contains a synthetic low-molecular-weight drug as the activeingredient, and at least one selected from the group consisting ofhydrophobic amino acids, hydrophobic dipeptides, and hydrophobictripeptides as the carrier.

615. The use of a freeze-dried composition for transpulmonaryadministration according to item 613, wherein the freeze-driedcomposition contains a high-molecular-weight drug such as a protein, apeptide or the like as the active ingredient, and at least one selectedfrom the group consisting of hydrophobic amino acids, hydrophobicdipeptides, and hydrophobic tripeptides as the carrier.

616. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition is a water-soluble composition.

617. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, using the dry powder inhaler ofitem 101 or 102 shown in the section of (1) Dry powder inhaler as thedevice.

618. The use of a freeze-dried composition for transpulmonaryadministration according to item 617, using the dry powder inhaler ofitem 109 shown in the section of (1) Dry powder inhaler as the device.

619. The use of a freeze-dried composition for transpulmonaryadministration according to item 602, wherein the freeze-driedcomposition has the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index in a range of 0.015 to 1.5, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of an air impact having an air speed in a range of        1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to        15 L/sec,        and the fine particles are made using a device comprising means        capable of applying the air impact to the freeze-dried        composition in the vessel and means for discharging the        resulting fine particle powder-form freeze-dried composition out        of the vessel.

620. The use of a freeze-dried composition in transpulmonaryadministration according to item 619, wherein the disintegration indexis 0.02 to 1.0.

621. The use of a freeze-dried composition in transpulmonaryadministration according to item 619, wherein the air speed is 1 to 250m/sec.

622. The use of a freeze-dried composition in transpulmonaryadministration according to item 619, wherein the air flow rate is 20ml/sec to 10 L/sec.

(7) Use of a Freeze-Dried Composition for Manufacture of a Dry PowderedPreparation for Transpulmonary Administration by Inhalation

Furthermore, the present invention provides use of a freeze-driedcomposition in a non-powder form for manufacture of a dry powderedpreparation for transpulmonary administration by inhalation. The useencompasses the specific embodiments defined in the following items 701to 723:

701. Use of a freeze-dried composition for manufacture of a dry powderedpreparation for transpulmonary administration by inhalation,

the freeze-dried composition having the following properties:

-   -   (i) has a non-powder cake-like form,    -   (ii) has a disintegration index of 0.015 or more, and    -   (iii) becomes fine particles having a mean particle diameter of        10 microns or less or a fine particle fraction of 10% or more        upon receipt of an air impact having an air speed of at least 1        m/sec and an air flow rate of at least 17 ml/sec,        and being used by forming into fine particles having said mean        particle diameter or said fine particle fraction at the time of        use.

702. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the disintegration index of the freeze-dried composition is0.02 or more.

703. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the disintegration index of the freeze-dried composition isin a range of 0.015 to 1.5.

704. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

705. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed in a range of 1 to 300 m/sec and an air flow rate of at least 17ml/sec.

706. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

707. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 10 microns or less or a fine particlefraction of 10% or more upon receipt of an air impact having an airspeed of at least 1 m/sec and an air flow rate in a range of 17 ml/secto 15 L/sec.

708. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition becomes fine particles havinga mean particle diameter of 5 microns or less or a fine particlefraction of 20% or more upon receipt of an air impact.

709. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as an active ingredient.

710. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as a protein, a peptide or the like asan active ingredient.

711. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item709, wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of amino acids, dipeptides,tripeptides, and saccharides as a carrier.

712. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item710, wherein the freeze-dried composition contains ahigh-molecular-weight drug such as a protein, a peptide or the like asthe active ingredient, and at least one selected from the groupconsisting of amino acids, dipeptides, tripeptides, and saccharides as acarrier.

713. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item711, wherein the freeze-dried composition contains a syntheticlow-molecular-weight drug as the active ingredient, and at least oneselected from the group consisting of hydrophobic amino acids,hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

714. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item712,

wherein the freeze-dried composition contains a high-molecular-weightdrug such as a protein, a peptide or the like as the active ingredient,and at least one selected from the group consisting of hydrophobic aminoacids, hydrophobic dipeptides, and hydrophobic tripeptides as thecarrier.

715. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition is a water-solublecomposition.

716. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the mean particle diameter of the fine particles of thepowdered preparation for transpulmonary administration is 5 microns orless or the fine particle fraction of the fine particles is 20% or more.

717. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, wherein the freeze-dried composition is housed in a vessel, and thefine particles are prepared by using a device comprising means forapplying a prescribed air impact to the freeze-dried composition housedin the vessel and means for discharging the resulting fine particlepowder form freeze-dried composition out of the vessel.

718. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration of item 717,using the dry powder inhaler according to item 101 or 102 shown in thesection of (1) Dry powder inhaler as the device.

719. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item718, using the dry powder inhaler of item 109 shown in the section of(1) Dry powder inhaler as the device.

720. The use of a freeze-dried composition for manufacture of a drypowdered preparation for transpulmonary administration according to item701, using the freeze-dried composition having the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.015 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10microns or less or a fine particle fraction of 10% or more uponreceiving an air impact having an air speed in a range of 1 to 300 m/secand an air flow rate in a range of 17 ml/sec to 15 L/sec.

721. The use of a freeze-dried composition for manufacture of a powderedpreparation for transpulmonary administration according to item 720,wherein the disintegration index is 0.02 to 1.0.

722. The use of a freeze-dried composition for manufacture of a powderedpreparation for transpulmonary administration according to item 720,wherein the air speed is 1 to 250 m/sec.

723. The use of a freeze-dried composition for manufacture of a powderedpreparation for transpulmonary administration according to item 720,wherein the air flow rate is 20 ml/sec to 10 L/sec.

EXAMPLES

Following is a detailed description of the present invention, citingexamples; however, the present invention is not limited to theseexamples.

In the following examples, the disintegration index of thenon-powder-form freeze-dried composition (freeze-dried cake) of thepresent invention, and the fine particle fraction (%), which is anindicator for evaluating the delivery into the lungs of the dry powderedpreparation produced, were calculated in accordance with the followingmethods.

<Calculation of Disintegration Index>

1.0 ml of n-hexane is instilled gently down the wall of the vessel intothe prepared non-powder-form freeze-dried composition (freeze-driedcake), and agitation is carried out for about 10 seconds at 3000 rpmusing an Automatic Lab-Mixer NS-8 (made by Pasolina). The mixtureobtained is put into a UV cell (made by Shimadzu GLC Center) of opticalpath length 1 mm and optical path width 10 mm, and then the turbidity ofthe mixture is measured immediately at a measurement wavelength of 500nm using a spectrophotometer (UV-240, made by Shimadzu Corporation). Thevalue obtained by dividing the turbidity obtained by the totalformulation amount (the total amount (weight) of the active ingredientand the carrier) is taken as the disintegration index.

<Calculation of Fine Particle Fraction>

A vessel filled with the prepared non-powder-form freeze-driedcomposition is installed into the dry powder inhaler, and using thedevice a prescribed air impact is applied on the composition, and thefine powdered preparation thus produced is discharged directly intoapparatus A (a twin impinger: made by Copley, UK) as mentioned in theEuropean Pharmacopoeia (Third Edition Supplement 2001, p 113-115). Afterthis, the solvents in stage 1 and stage 2 of the apparatus arerespectively collected, and the active ingredient contained in eachsolvent in the stage 1 or stage 2 is assayed using an appropriate methodin accordance with the type of active ingredient in the freeze-driedcomposition, for example a bioassay method or HPLC (see the report ofLucas et al. (Pharm. Res., 15 (4), 562-569 (1998)) and the report ofIida et al. (Yakugaku Zasshi, 119 (10), 752-762 (1999)). The fractionthat can be expected to be delivered into the lungs is that in stage 2(the aerodynamic diameter of particles recovered in this fraction is 6.4μm or less); the proportion of the active ingredient that reaches stage2 and is recovered here is generally called the fine particle fraction(the amount that can be expected to reach the lungs), and is taken as ayardstick for evaluating the suitability as an inhalation fortranspulmonary administration.

In the Examples and Comparative Examples given below, the activeingredients contained in stage 1 and stage 2 were quantitated, and theweight amount of the active ingredient in stage 2 was divided by thetotal weight amount of the active ingredients jetted out (the totalweight amount of the active ingredients contained in stage 1 and stage2: hereinafter also referred to as “Stage 1+Stage 2”) to calculate fineparticles fraction. Moreover, as a rule in the European Pharmacopoeia,when using the twin impinger (made by Copley, UK), it is stipulated thatsuction is carried out at an air suction flow rate of 60 L/min, i.e. 1L/sec, and hence in the examples and comparative examples below this wasfollowed.

Embodiment 1 Dry Powder Inhaler (Jet Type 1)

A description of an embodiment of the jet type dry powder inhaler usedin the present invention will now be given using FIG. 1. The dry powderinhaler is an air jet type apparatus for breaking down into fineparticles and delivering into the lungs a unit or a plurality of dosesof a non-powder-form freeze-dried composition 2 housed at the bottom ofa vessel 1, and comprises a needle 5 that has an air jet flow path 3 anda discharge flow path 4, an air intake member 7 that has an inhalationport 6 and is attached to a base end of the needle part 5, a tubularsafety cover 8 that surrounds the needle part 5 and also holds thevessel 1, and air pressure-feeding means 9.

The air pressure-feeding means 9 is manually operated and comprises atubular bellows body 10. An intake port 12 equipped with an intake valve11, and a discharge port 14 equipped with a discharge valve 13 areprovided in the bellows body 10. The discharge port 14 is attached to aconnecting port, 15 formed at the base end of the air jet flow path 3 ofthe needle part 5, and communicates with the air jet flow path 3. Byapplying a compressive force to the bellows body 10 and thus contractingthe bellows body 10 in a state in which the intake valve 11 is closed,the discharge valve 13 is opened, and air in the bellows body 10 isdischarged into the vessel 1 from the discharge port 14 via the air jetflow path 3. When the compressive force is released, on the other hand,the bellows body 10 expands due to the elastic restoring force of thebellows body 10, and in a state in which the discharge valve 13 isclosed, the intake valve 11 opens, and air is introduced into thebellows body 10.

When using the dry powder inhaler, as shown in FIG. 1, the vessel 1 isinserted into the tubular safety cover 8, and a stopper 1 a of thevessel 1 is pierced by the needle part 5, thus communicating the air jetflow path 3 and the discharge flow path 4 with the inside of the vessel1. In this state, if the bellows body 10 of the air pressure-feedingmeans 9 is contracted to discharge air from the discharge port 14, thenthis air passes through the air jet flow path 3 and is jetted out fromthe tip of the needle part 5 towards the freeze-dried composition 2 inthe vessel, and due to the resulting air impact the freeze-driedcomposition 2 becomes fine particles, which then pass through thedischarge flow path 4 of the needle part 5 and are discharged from theinhalation port 6 of the air intake member 7. The user (patient) inhalesthese fine particles from the inhalation port 6 of the air intakemember, whereupon the fine particles of the freeze-dried composition 2are delivered into the lungs of the user (patient). The material of thestopper of the vessel for use in the invention is not limited, and canbe selected from materials usually used for a stopper of a vessel forholding a drug or compound, such as rubber, plastic, aluminum or thelike.

With this jet type dry powder inhaler, the air jet amount is set to beabout 20 ml, the volume of the vessel about 5 ml, the bore (diameter) ofthe air jet flow path 3 about 1.2 mm, and the bore (diameter) of thedischarge flow path 4 about 1.8 mm.

Note, however, that there is no limitation to this. The preferable rangefor the bores of the air jet flow path 3 and the discharge flow path 4varies according to the size of the vessel and so on. These bores can beselected as appropriate from a range of 0.3 to 10 mm, preferably 0.3 to7 mm, more preferably 0.5 to 5 mm.

Moreover, regarding the air pressure-feeding means 9, the dischargeamount of fine particles required for administration by inhalation canbe adjusted by adjusting the speed of compression of the bellows body10. Adjustment can also be carried out by such air jet such that most ofthe freeze-dried composition 2 is broken down into fine particles.

Embodiment 2 Dry Powder Inhaler (Self-Inhaling Type 1)

A description of an embodiment (first embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIG. 2. The dry powder inhaler shown in FIG. 2 comprises a needlepart 5 having a suction flow path 16 and an air introduction flow path17, a tubular safety cover 8, and an air intake member 19 that has aninhalation port 18 and communicates with the suction flow path 16. Theair intake member 19 is connected to the base end of the suction flowpath 16 of the needle part 5.

When using the dry powder inhaler, as shown in FIG. 2, the vessel 1 isinserted into the tubular safety cover 8, and an stopper 1 a of thevessel 1 is pierced by the needle part 5, thus communicating the suctionflow path 16 and the air introduction flow path 17 with the inside ofthe vessel 1. In this state, through the inhalation pressure of the user(patient), air in the vessel 1 is sucked in from the inhalation port 18via the suction flow path 16, and at the same time outside air flowsinto the vessel 1, which is now at a negative pressure, from the airintroduction flow path 17. At this time, the freeze-dried composition 2is made into fine particles through the air impact acting on thefreeze-dried composition 2, and the fine particles produced aredelivered into the user's (patient's) lungs from the inhalation port 18via the suction flow path 16.

Moreover, with this dry powder inhaler, setting is carried out such thatmost of the freeze-dried composition 2 is made into fine particles anddischarged from the inhalation port 18 through one inhalation of theuser (patient). It is considered that the air flow rate of oneinhalation of the user (patient) is 5 to 300 L/min, preferably 10 to 200L/min, more preferably 10 to 100 L/min, but the design of theself-inhaling type dry powder inhaler of the present invention ismodified as appropriate in accordance with the respiratory ability ofthe user (patient) using the device. With the dry powder inhaler shownin FIG. 2, in accordance with the respiratory ability of the user(patient) in question, the volume of the vessel has been set to about 10ml, and the bores of the air introduction flow path 17 and the suctionflow path 16 to about 1.5 mm. As a result, the settings are such thatthe freeze-dried composition 2 is made into fine particles anddischarged from the inhalation port 18 with virtually none left behindthrough one inhalation of the user (patient).

Embodiment 3 Dry Powder Inhaler (Self-Inhaling Type 2)

A description of an embodiment (second embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIG. 3. The dry powder inhaler shown in FIG. 3 is the same as thejet type dry powder inhaler shown in FIG. 1 with the bellows body 10used for pressure-feeding air removed from the connecting port 15. Thedischarge flow path 4 of the jet type dry powder inhaler of FIG. 1corresponds to a suction flow path 16, the air jet flow path 3 to an airintroduction flow path 17, and the air intake member 7 having theinhalation port 6 to an air intake member 19 having an inhalation port18.

When using the self-inhaling type dry powder inhaler in question, themain points are the same as with the dry powder inhaler shown in FIG. 2.Through the inhalation pressure of the user (patient), air in the vessel1 is sucked in from the inhalation port 18 via the suction flow path 16,and at the same time outside air flows into the vessel 1, which is nowat a negative pressure, from the air introduction flow path 17. Thefreeze-dried composition 2 is made into fine particles through the airimpact produced accompanying this inflow of air. The fine particlesproduced are then delivered into the user (patient's) lungs from theinhalation port 18. As mentioned before, the air flow rate for oneinhalation of the user (patient) is generally in a range of 5 to 300L/minute; however, with the dry powder inhaler shown in FIG. 3, inaccordance with the respiratory ability of the user (patient) inquestion, the volume of the vessel was set to about 5 ml, the bore(diameter) of the air introduction flow path 17 to about 1.2 mm, and thebore (diameter) of the suction flow path 16 to about 1.8 mm. As aresult, the settings are such that most of the freeze-dried composition2 is made into fine particles and discharged from the inhalation port 18through one inhalation of the user (patient).

If the self-inhaling type dry powder inhaler is constituted in this way,then by detachably installing air pressure-feeding means 9 such as abellows body 10 into the connecting port 15, the self-inhaling type drypowder inhaler can be changed into a jet type. A single dry powderinhaler can thus be used as either a self-inhaling type or a jet type asdesired.

Each of the above dry powder inhalers of the present invention,regardless of whether it is a self-inhaling type or a jet type, can beconstituted such that it is possible to select and set the size of theair impact such that the freeze-dried composition becomes fine particlesof mean particle diameter 10 microns or less, preferably 5 microns orless, and flies out with almost none left behind.

Embodiment 4 Dry Powder Inhaler (Self-Inhaling Type 3)

A description of an embodiment (third embodiment) of the self-inhalingtype dry powder inhaler used in the present invention will now be givenusing FIGS. 4 to 10. FIG. 4 is a perspective view showing the dry powderinhaler, and FIG. 5 is a sectional view showing the dry powder inhaler.Moreover, FIG. 6( a) is a partial sectional view showing a needle part 5and a suction port 31 of the dry powder inhaler, and (b) is a side viewof the needle part 5. Furthermore, FIGS. 7 to 10 are sectional views forexplaining the operation of the dry powder inhaler.

The dry powder inhaler comprises a needle part 5 in which are formed asuction flow path 16 and an air introduction flow path 17, a holder part22 for holding a vessel 1, a housing chamber 20 for housing the vessel 1via the holder part 22, a guide part 23 provided in the housing chamber20 for guiding the holder part 22 in the axial direction of the needlepart 5, and a holder operating part 24 for advancing and retreating theholder part 22 along the guide part 23; these are all housed in atubular housing 21. Moreover, a mouthpiece 32 that has a suction port 31and communicates with the suction flow path 16 of the needle part 5 isprovided at a tip of the housing 21.

As shown in FIG. 7, in detail the housing 21 is formed from a housingmain body 26 in which is formed a removal/insertion port 25 in aposition in which the holder part 22 is retreated, and a lid 27 thatopens and closes the removal/insertion port 25. The lid 27 is connectedto the housing main body 26 by a hinge 21A, and a window 28 forverifying whether the vessel 1 has been loaded is provided in the lid27.

An introduction port 29 for introducing outside air is provided in awall of the housing 21, and a check valve 30 is installed at theintroduction port 29. Moreover, the mouthpiece 32 is provided at the tipof the housing 21. The suction port 31 of the mouthpiece 32 is coveredby a cap 32 a when the dry powder inhaler is not being used.

A flange-shaped partition part 33 is formed at the base end of theneedle part 5, and an end of the air introduction flow path 17 passesthrough the partition part 33 and opens out in an outer peripheraldirection of the partition part 33. Moreover, a peripheral wall part 34extends from an outer rim part of the partition part 33 towards thesuction port 31 of the mouthpiece 32. The needle part 5 is installedinto the housing 21 by fitting the partition part 33 into the tip partof the housing 21. Through this installation, the axial direction of thehousing 21 and the axial direction of the needle part 5 are aligned withone another.

A remover 35 for lifting the vessel 1 up from the base of the holderpart 22 and removing the vessel 1 is attached to the holder part 22, anda lever 36 for lifting the vessel 1 up is formed on the remover 35.

The holder operating part 24 comprises a mechanism part 37 for movingthe holder part 22 back and forth along the axial direction of thehousing 21, and an operating lever for operating the mechanism part 37.The mechanism part 37 comprises a connector 39. One end of the connector39 is connected to the holder part 22 by a hinge 40, and the other endof the connector 39 is connected to the lid 27 by a hinge 41. The lid 27is also used as the above-mentioned operating lever. By opening andclosing the lid 27, the holder part 22 is advanced and retreated alongthe guide part 23.

The point of action of the force for pushing down the lid 27 is shown bythe arrow C in FIG. 7. That is, the distance from the hinge 21A to thepoint of action is made to be longer than the distance from the hinge21A to the hinge 41. As a result, through the lever principle, the lid(operating lever) 27 can be operated by a force smaller than the forcenecessary to pierce the stopper 1 a of the vessel 1 with the needle part5.

Moreover, as shown in FIG. 6, second introduction paths 42 forsupplementary introduction of air are formed in the dry powder inhaler.When sucking the freeze-dried composition that has been made into apowder from the mouthpiece 32, outside air passes through these secondintroduction path 42 and flows to the suction port 31 of the mouthpiece32. As a result, the dry powder inhaler can be used without imposing aburden even by a user (patient) having reduced pulmonary capacity or achild patient. Note that the second introduction paths 42 may beomitted.

Introduction grooves 42 a are provided in the partition part 33 of theneedle part 5 and introduction grooves 42 b are provided in theperipheral wall part 34. By fitting the mouthpiece 32 into theperipheral wall part 34 of the needle part 5, the second introductionpaths 42 are thus formed from the mouthpiece 32 and the introductiongrooves 42 a and 42 b.

A slight gap 43 is formed between the mouthpiece 32 and the housing 21,and one end 44 of the second introduction paths 42 opens out to theoutside via the gap 43, while the other end 45 of the secondintroduction paths 42 opens out into the suction port 31 of themouthpiece 32.

Moreover, as shown in FIG. 6, a wall 47 having vent holes 46 is providedin the suction port 31. Consequently, even in the case that the airimpact applied to the freeze-dried composition 2 is small due to a lackof suction force or the like, and part of the freeze-dried composition 2is not made into a powder, the non-powder part can be made into a powderwhen passing through the vent holes 46 of the wall 47.

Moreover, as shown in FIG. 6( a), a tip opening 17 a of the airintroduction flow path 17 of the needle part is made to be closer to thefreeze-dried composition 2 than a tip opening 16 a of the suction flowpath 16. As a result, dropping of the flow speed of the air that flowsinto the vessel 1 from the tip opening 17 a of the air introduction flowpath 17 can be suppressed as much as possible, and hence an effectiveair impact can be applied to the freeze-dried composition 2. Moreover,because the tip opening 16 a of the suction flow path 16 of the needlepart 5 is further from the freeze-dried composition 2 than the tipopening 17 a of the air introduction flow path 17, making of thefreeze-dried composition 2 can be made to into a fine powder in thevessel 1 as much as possible before being sucked into the airintroduction flow path 16 of the needle part 5.

The dry powder inhaler is used as follows. Firstly, the lid 27 is liftedup to open the removal/insertion port 25 of the housing 21 as in FIG. 7,whereby the holder part 22 is pulled backwards to reach theremoval/insertion port 25 of the housing 21. Next, the vessel 1 isinstalled in the holder part 22 with the stopper 1 a facing forwards.Next, the lid 27 is pushed down to close the removal/insertion port 25of the housing 21 as in FIG. 8, whereby the holder part 22 is pushedtowards the needle part 5 by the connector 39, and the stopper 1 a ofthe vessel 1 is pierced by the tip of the needle part 5, thuscommunicating the suction flow path 16 and the air introduction flowpath 17 of the needle part 5 with the inside of the vessel 1. Next, airin the vessel 1 is sucked from the suction port 31 of the mouthpiece 32through the suction flow path 16 of the needle part 5 by the inhalationpressure of the user (patient). At this time, the inside of the vessel 1becomes a negative pressure and the check valve 30 opens, and outsideair flows into the vessel 1 through the air introduction flow path 17 ofthe needle part 5. As a result, an air impact is generated in the vessel1 and the freeze-dried composition 2 is broken down into fine particles,and the fine particles prepared are delivered into the user's(patient's) lungs from the suction port 31 via the suction flow path 16.After use, the lid 27 is lifted up to pull the holder part 22 back up tothe removal/insertion port 25 of the housing 21, and then the remover 35is lifted up by the lever 36 and the vessel 1 is removed from the holderpart 22.

Even if air is conversely blown into the vessel 1 from the suction port31 of the mouthpiece 32, discharge to the outside of the freeze-driedcomposition 2 made into fine particles is prevented by the check valve30.

As mentioned before, the air flow rate of one inhalation of the user(patient) is generally in a range of 5 to 300 L/min, but with the drypowder inhaler shown in FIGS. 4 to 10, in accordance with therespiratory ability of the user (patient), the volume of the vessel 1has been set to about 5 ml, the bore (diameter) of the air introductionflow path 17 to about 2.5 mm, and the bore (diameter) of the suctionflow path 16 to about 2.5 mm. As a result, the settings are such thatmost of the freeze-dried composition 2 is made into fine particles anddischarged from the suction port 31 through one inhalation of the user(patient).

Other embodiments of the dry powder inhaler (self-inhaling type) areshown in FIGS. 11 to 13.

With the dry powder inhaler (self-inhaling type 4) shown in FIG. 11, anoperating member 48 is provided so as to be freely rotatable in thecircumferential direction of the housing 21 as shown by the arrow. Themechanism part of the holder operating part, which is not shown in thedrawing, comprises a spiral groove and a follower that engages into thesame; when the operating member 48 is rotated, this rotation isconverted to linear movement of the holder part 22 in the axialdirection of the needle part 5. Note that the angle of rotation of theoperator 48 is about 180°.

With the dry powder inhaler (self-inhaling type 5) shown in FIG. 12 andFIG. 13, an annular operating member 49 is installed so as to be freelyrotatable in the housing 21. The mechanism part of the holder operatingpart, which is not shown in the drawing, comprises a feed screw; whenthe operating member 49 is rotated, this rotation is converted to linearmovement of the holder part 22 in the axial direction of the needle part5. The holder part 22 can be withdrawn from the back of the housing 21.

Examples 1 to 13, Comparative Examples 1 to 4

An interferon-α (IFN-α) stock liquid (potency: 2×10⁷ IU/ml) wasdesalinated using an ultrafilter membrane (Ultrafree 15, made byMillipore). 0.25 ml of the desalinated IFN-α stock liquid obtained and 2mg of any of various carriers as shown in Table 1 were filled intovessels (trunk diameter 18 mm), being made up with distilled water for ainjection (injection distilled water) such that the volume was 0.5 mlper vessel, and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form (cake-like) freeze-dried composition (freeze-driedcake) obtained was calculated. Next, a vessel containing thenon-powder-form freeze-dried composition (freeze-dried cake) obtainedwas installed in a jet type dry powder inhaler (having a bellows body 10capable of supplying an amount of air of about 20 ml; FIG. 1) designedsuch that the bore of the air jet flow path 3 was 1.2 mm and the bore ofthe discharge flow path 4 was 1.8 mm.

It was verified that, by introducing an amount of air of about 20 mlfrom the dry powder inhaler into the vessel (giving an air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec), the non-powder-form freeze-dried cake in the vesselwas made into fine particles, and the fine particles were jetted outfrom the vessel via the discharge flow path 4 in an instant. The fineparticles were collected using a particle size distribution meter(Aerosizer: made by Amherst Process Instrument, Inc., USA; R. W. Niven:Pharmaceutical Technology, 72-78 (1993)) fitted with an Aerobreather(made by Amherst Process Instrument, Inc., USA, R. W. Niven:Pharmaceutical Technology, 72-78 (1993)), which is an artificial lungmodel capable of directly measuring the particle size distribution ofthe particles jetted out from the vessel (measurement conditions: breathrate: 60 L/min, breath volume: 1 L, acceleration: 19); the particle sizedistribution of the fine particles that had been made was thus measured,and the mass median aerodynamic diameter (μm±SD) was calculated from theparticle size distribution. The disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 1 for each of the freeze-driedcompositions.

TABLE 1 Mass median Freeze-dried Disintegration aerodynamic diametercomposition index (μm ± SD, MMAD) Examples 1. IFN-α + isoleucine 0.2251.614 ± 1.590 2. IFN-α + valine 0.173 1.091 ± 1.390 3. IFN-α + leucine0.221 1.120 ± 1.416 4. IFN-α + phenylalanine 0.264 1.053 ± 1.405 5.IFN-α + alanine 0.168 1.456 ± 1.403 6. IFN-α + glycine 0.171 1.951 ±1.419 7. IFN-α + β-alanine 0.109 2.420 ± 1.525 8. IFN-α + γ-aminobutyricacid 0.139 2.103 ± 1.546 9. IFN-α + taurine 0.136 2.132 ± 1.526 10. IFN-α + D-mannitol 0.180 2.128 ± 1.575 11.  IFN-α + lactose 0.077 2.848± 1.837 12.  IFN-α + β-cyclodextrin 0.176 3.700 ± 1.526 13.  IFN-α +PEG4000 0.161 2.759 ± 1.577 Comparative Examples 1. IFN-α + dextran 400.002 Didn't scatter at all, measurement impossible 2. IFN-α + dextran70 0.002 Didn't scatter at all, measurement impossible 3. IFN-α +chondroitin sulfate 0.001 Didn't scatter at all, measurement impossible4. IFN-α + pullulan 0.001 Didn't scatter at all, measurement impossible

For all of the examples and comparative examples, the freeze-driedcomposition containing the IFN-α and the carrier shown in Table 1 was anon-powder-form cake-like mass (freeze-dried cake) at the time offreeze-drying. As can be seen from Table 1, the non-powder-formfreeze-dried cakes having a disintegration index of 0.002 or less(Comparative Examples 1 to 4) were not disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, and hence it was not possible to make fine particles.On the other hand, the non-powder-form freeze-dried cakes showing adisintegration index of 0.077 or more (Examples 1 to 13) weredisintegrated by the air impact arising through an air speed of about 35m/sec and an air flow rate of about 40 ml/sec, becoming fine particlesof mass median aerodynamic diameter less than 5 microns, i.e. becoming afine-particle-form powdered preparation suitable for transpulmonaryadministration.

For Examples 1, 2, 3, 4, 5 and 6, the particle size distributions of thefine particles jetted out from the dry powder inhaler are shown in FIGS.14, 15, 16, 17, 18 and 19 respectively.

Examples 14 to 26, Comparative Examples 5 to 8

5 μl of an interleukin-1α (IL-1α) stock liquid (potency: 1×10⁸ U/ml) and2 mg of any of various carriers as shown in Table 2 were filled intovessels (trunk diameter 18 mm), being made up with injection distilledwater such that the volume was 0.5 ml per vessel, and freeze-drying wascarried out using a shelf-type freeze-dryer (Lyovac GT-4, made byLeybold). The disintegration index of the non-powder-form (cake-like)freeze-dried composition (freeze-dried cake) obtained was calculated.Next, a vessel filled with the non-powder-form freeze-dried composition(freeze-dried cake) obtained was installed in a jet type dry powderinhaler (having a bellows body 10 capable of supplying an amount of airof about 20 ml; FIG. 1) designed such that the bore of the air jet flowpath 3 was 1.2 mm and the bore of the discharge flow path 4 was 1.8 mm.

As in Examples 1 to 13, this inhaler was attached to an Aerosizer (madeby Amherst Process Instrument, Inc., USA) fitted with an Aerobreather,which is an artificial lung model, and an amount of air of about 20 mlwas introduced into the vessel from the inhaler, thus applying an airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec to the freeze-dried cake. As a result, air wasintroduced from the air jet flow path 3 of the jet type dry powderinhaler into the vessel 1, and it was observed that the non-powder-formfreeze-dried composition in the vessel was made into fine particles bythe air impact. The particle size distribution of the fine particles wasmeasured using the Aerosizer fitted with the Aerobreather (measurementconditions: breath rate: 60 L/min, breath volume: 1 L, acceleration:19). The mass median aerodynamic diameter (μm±SD) was then calculatedfrom the particle size distribution of the fine particles jetted outfrom the inhaler. The disintegration index and the mass medianaerodynamic diameter (μm±SD) are shown in Table 2 for each of thefreeze-dried compositions.

TABLE 2 Mass median Freeze-dried Disintegration aerodynamic diametercomposition index (μm ± SD, MMAD) Examples 14. IL-1α + isoleucine 0.1721.539 ± 1.527 15. IL-1α + valine 0.195 1.337 ± 1.440 16. IL-1α + leucine0.220 1.115 ± 1.464 17. IL-1α + phenylalanine 0.314 1.391 ± 1.496 18.IL-1α + alanine 0.129 2.070 ± 1.647 19. IL-1α + glycine 0.110 1.978 ±1.420 20. IL-1α + β-alanine 0.106 2.204 ± 1.509 21. IL-1α +γ-aminobutyric acid 0.166 2.149 ± 1.534 22. IL-1α + taurine 0.147 2.026± 1.520 23. IL-1α + D-mannitol 0.124 1.765 ± 1.460 24. IL-1α + lactose0.097 3.681 ± 1.851 25. IL-1α + β-cyclodextrin 0.178 3.234 ± 1.515 26.IL-1α + PEG4000 0.116 2.494 ± 1.547 Comparative Examples  5. IL-1α +dextran 40 0.001 Didn't scatter at all, measurement impossible  6.IL-1α + dextran 70 0.002 Didn't scatter at all, measurement impossible 7. IL-1α + chondroitin sulfate 0.001 Didn't scatter at all, measurementimpossible  8. IL-1α + pullulan 0.001 Didn't scatter at all, measurementimpossible

Each of the freeze-dried compositions containing the IL-1α and thecarrier shown in Table 2 was a non-powder-form cake-like mass(freeze-dried cake) at the time of freeze-drying. As can be seen fromTable 2, the non-powder-form freeze-dried cakes having a disintegrationindex of 0.002 or less (Comparative Examples 5 to 8) were notdisintegrated by the air impact arising through an air speed of about 35m/sec and an air flow rate of about 40 ml/sec, and hence it was notpossible to make fine particles. On the other hand, the non-powder-formfreeze-dried cakes showing a disintegration index of 0.097 or more(Examples 14 to 26) were disintegrated by the air impact arising throughan air speed of about 35 m/sec and an air flow rate of about 40 ml/sec,becoming fine particles of mass median aerodynamic diameter less than 5microns, i.e. becoming a fine-particle-form powdered preparationsuitable for transpulmonary administration.

Examples 27 to 37

An interferon-γ (IFN-γ) stock liquid (potency: 1×10⁷ IU/ml) wasdesalinated using an ultrafilter membrane (Ultrafree 15, made byMillipore). 0.01 ml of the desalinated IFN-γ stock liquid obtained andany of various carriers as shown in Table 3 were filled into vessels(trunk diameter 18 mm), the volume was made up with injection distilledwater to 0.5 ml per vessel, and freeze-drying was carried out using ashelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form (cake-like) freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, a vesselfilled with the non-powder-form freeze-dried composition (freeze-driedcake) obtained was installed in a jet type dry powder inhaler (having abellows body 10 capable of supplying an amount of air of about 20 ml;FIG. 1) designed such that the bore of the air jet flow path 3 was 1.2mm and the bore of the discharge flow path 4 was 1.8 mm.

As in Examples 1 to 13, this inhaler was attached to an Aerosizer (madeby Amherst Process Instrument, Inc., USA) fitted with an Aerobreather,which is an artificial lung model, and an amount of air of about 20 mlwas introduced into the vessel from the inhaler, thus applying an airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec to the freeze-dried cake. As a result, air wasintroduced from the air jet flow path 3 of the jet type dry powderinhaler into the vessel 1, and it was observed that the non-powder-formfreeze-dried composition in the vessel was made into fine particles bythe air impact. The particle size distribution of the fine particles wasmeasured using the Aerosizer fitted with the Aerobreather (measurementconditions: breath rate: 60 L/min, breath volume: 1 L, acceleration:19). The mass median aerodynamic diameter (μm±SD) was then calculatedfrom the particle size distribution of the fine particles jetted outfrom the inhaler.

Moreover, to calculate the fine particle fraction (%) of the fineparticles for each freeze-dried composition and thus evaluate theefficiency of delivery into the lungs, an air impact arising through anair speed of about 35 m/sec and an air flow rate of about 40 ml/sec wasapplied to the freeze-dried cake filled into a vessel using the drypowder inhaler, and the resulting powdered fine-particle-formfreeze-dried composition was discharged directly into a twin impinger(made by Copley, UK). After this, the solvents in stage 1 and stage 2were collected, the IFN-γ in the stage 1 and stage 2 solvents wereassayed using a bioassay method. The value obtained by dividing theamount (weight) of IFN-γ obtained in stage 2 by the total amount(weight) of IFN-γ jetted out (stage 1+stage 2) was then calculated asthe fine particle fraction (%). The disintegration index, the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the device, and the fine particle fraction (%) are shown in Table 3for each of the freeze-dried compositions.

TABLE 3 Mass median aerodynamic Freeze-dried Disintegration diameterFine particle Composition index (μm ± SD, MMAD) fraction (%) 27. IFN-γ +Leu (2.5 mg) 0.197 1.814 ± 1.538 72.0 28. IFN-γ + Val (2.5 mg) 0.2071.553 ± 1.451 50.2 29. IFN-γ + Ile (2.5 mg) 0.185 1.652 ± 1.479 53.0 30.IFN-γ + Phe (2.5 mg) 0.215 1.322 ± 1.443 74.0 31. IFN-γ + Leu (0.5 mg) +Val (2 mg) 0.199 1.504 ± 1.461 51.4 32. IFN-γ + Leu (0.48 mg) + Val(1.92 mg) + 0.159 1.500 ± 1.464 52.0 Arg-HCl (0.2 mg) 33. IFN-γ + Phe(1.2 mg) + Leu (0.3 mg) + 0.191 1.264 ± 1.383 67.0 Arg-HCl (0.2 mg) 34.IFN-γ + Phe (1.2 mg) + Val (0.3 mg) + 0.190 1.350 ± 1.456 64.0 Arg-HCl(0.2 mg) 35. IFN-γ + Phe (1.2 mg) + Ile (0.3 mg) + 0.181 1.230 ± 1.38667.0 Arg-HCl (0.2 mg) 36. IFN-γ + Phe (1.0 mg) + 0.269 1.280 ± 1.47359.0 Arg-HCl (0.2 mg) 37. IFN-γ + Leu (1.5 mg) + Val (1.0 mg) + 0.1911.545 ± 1.405 45.4 D-mannitol (1.0 mg) Leu: leucine, Val: valine, Ile:isoleucine, Phe: phenylalanine, Arg-HCl: arginine hydrochloride

Each of the freeze-dried compositions containing the IFN-γ and thecarrier shown in Table 3 was a non-powder-form cake-like mass(freeze-dried cake) at the time of freeze-drying. As can be seen fromTable 3, the non-powder-form freeze-dried cakes showing a disintegrationindex of 0.159 or more (Examples 27 to 37) were disintegrated by the airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming afine-particle-form powdered preparation suitable for transpulmonaryadministration. Moreover, a good fine particle fraction was obtained forall of the compositions (IFN-γ carrier).

Examples 38 to 48, Comparative Examples 9 to 10

5 μg of procaterol hydrochloride (made by Otsuka Pharmaceutical Co.,Ltd.) and 1.5 mg of any of various carriers as shown in Table 4 weremade up to 0.5 ml by dissolving in injection distilled water, this wasfilled into vessels (trunk diameter 18 mm), and freeze-drying wascarried out using a shelf-type freeze-dryer (Lyovac GT-4, made byLeybold). The disintegration index of the non-powder-form (cake-like)freeze-dried composition (freeze-dried cake) obtained was calculated.Next, a vessel (trunk diameter 18 mm) filled with the non-powder-formfreeze-dried cake obtained was installed in a self-inhaling type drypowder inhaler designed such that the bore of the air introduction flowpath 17 was 1.99 mm and the bore of the suction flow path 16 was 1.99mm.

To evaluate the delivery into the lungs of the freeze-dried compositionobtained, the above-mentioned self-inhaling type dry powder inhaler wasattached to a twin impinger (made by Copley, UK) (applying an air impactarising through an air speed of about 95 m/sec and an air flow rate ofabout 295 ml/sec to the freeze-dried cake), the solvents in stage 1 andstage 2 were respectively collected, and each of the procaterolhydrochloride contained in the stage 1 or stage 2 solvent was assayed byan HPLC method. The value obtained by dividing the amount of procaterolhydrochloride obtained in stage 2 by the total amount of procaterolhydrochloride jetted out (stage 1+stage 2) was then calculated as thefine particle fraction (%, the proportion that can be expected to reachthe lungs).

The disintegration index and the fine particle fraction (%) are shown inTable 4 for each of the freeze-dried compositions.

TABLE 4 Fine particle Disintegration fraction Freeze-dried compositionindex (%) Examples 38. Procaterol-HCl + isoleucine 0.199 61.1 39.Procaterol-HCl + valine 0.270 71.9 40. Procaterol-HCl + leucine 0.26074.0 41. Procaterol-HCl + phenylalanine 0.245 70.8 42. Procaterol-HCl +alanine 0.048 61.6 43. Procaterol-HCl + glycine 0.139 60.6 44.Procaterol-HCl + taurine 0.110 63.3 45. Procaterol-HCl + D-mannitol0.144 60.7 46. Procaterol-HCl + β-cyclodextrin 0.138 69.1 47.Procaterol-HCl + PEG4000 0.102 63.6 48. Procaterol-HCl + sodium caprate0.222 73.4 Comparative Examples  9. Procaterol-HCl + pullulan 0.001 0.010. Procaterol-HCl + dextran 40 0.003 0.0 Procaterol-HCl: Procaterolhydrochloride

As shown in Table 4, the non-powder-form freeze-dried compositions(freeze-dried cakes) having a disintegration index of 0.003 or less(Comparative Examples 9 and 10) were not disintegrated by the air impactarising through an air speed of about 95 m/sec and an air flow rate ofabout 295 ml/sec, whereas the non-powder-form freeze-dried compositions(freeze-dried cakes) having a disintegration index of 0.048 or more wereeasily made into fine particles in the vessel by the above-mentioned airimpact, with it being possible to produce a powdered preparationsuitable for transpulmonary administration.

Examples 49 to 58, Comparative Examples 11 to 14

5 μg of procaterol hydrochloride (made by Otsuka Pharmaceutical Co.,Ltd.) and any of various carriers as shown in Table 5 were made up to0.5 ml by dissolving in injection distilled water, this was filled intovessels (trunk diameter 18 mm), and freeze-drying was carried out usinga shelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated.

Next, as with Examples 38 to 48, a vessel (trunk diameter 18 mm) filledwith the non-powder-form freeze-dried composition obtained was installedin a self-inhaling type dry powder inhaler designed such that the boreof the air introduction flow path 17 was 1.99 mm and the bore of thesuction flow path 16 was 1.99 mm. Using this, the fine particle fraction(%) was calculated with a twin impinger (made by Copley, UK) (applyingan air impact arising through an air speed of about 95 m/sec and an airflow rate of about 295 ml/sec to the freeze-dried cake). Thedisintegration index and the fine particle fraction (%) are shown inTable 5 for each of the freeze-dried compositions.

TABLE 5 Disintegration Fine particle Freeze-dried composition indexfraction (%) Examples 49. Procaterol-HCl + 4.5 mg isoleucine 0.170 57.250. Procaterol-HCl + 7.5 mg isoleucine 0.156 52.8 51. Procaterol-HCl +4.5 mg leucine 0.214 74.0 52. Procaterol-HCl + 7.5 mg leucine 0.191 58.053. Procaterol-HCl + 4.5 mg valine 0.174 62.0 54. Procaterol-HCl + 4.5mg phenylalanine 0.237 56.9 55. Procaterol-HCl + 4.5 mg PEG4000 0.15252.5 56. Procaterol-HCl + 4.5 mg sodium caprate 0.168 51.4 57.Procaterol-HCl + 4.5 mg alanine 0.023 58.5 58. Procaterol-HCl + 7.5 mgalanine 0.018 50.7 Comparative Examples 11. Procaterol-HCl + 4.5 mgpullulan 0.0003 0.0 12. Procaterol-HCl + 7.5 mg pullulan 0.0002 0.0 13.Procaterol-HCl + 4.5 mg dextran 40 0.0013 0.0 14. Procaterol-HCl + 7.5mg dextran 40 0.0010 0.0 Procaterol-HCl: Procaterol hydrochloride

As shown in Table 5, the non-powder-form freeze-dried compositions(freeze-dried cakes) having a disintegration index of 0.0013 or less(Comparative Examples 11 to 14) were not disintegrated by the air impactarising through an air speed of about 95 m/sec and an air flow rate ofabout 295 ml/sec, whereas the non-powder-form freeze-dried compositions(freeze-dried cakes) showing a disintegration index of 0.018 or more(Examples 49 to 58) were easily made into fine particles in the vesselby the above-mentioned air impact, with it being possible to produce apowdered preparation suitable for transpulmonary administration.

Examples 59 to 64

5 μg of procaterol hydrochloride (made by Otsuka Pharmaceutical Co.,Ltd.) and any of various carriers as shown in Table 6 were made up to0.5 ml by dissolving in injection distilled water, this was filled intovessels (trunk diameter 18 mm), and freeze-drying was carried out usinga shelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, as withExamples 38 to 48, a vessel (trunk diameter 18 mm) filled with thenon-powder-form freeze-dried composition obtained was installed in aself-inhaling type dry powder inhaler designed such that the bore of theair introduction flow path 17 was 1.99 mm and the bore of the suctionflow path 16 was 1.99 mm. Using this, the fine particle fraction (%) wascalculated with a twin impinger (made by Copley, UK) (applying an airimpact arising through an air speed of about 95 m/sec and an air flowrate of about 295 ml/sec to the freeze-dried cake) The disintegrationindex and the fine particle fraction (%) are shown in Table 6 for eachof the freeze-dried compositions.

TABLE 6 Disintegration Fine particle Freeze-dried composition indexfraction (%) 59. Procaterol-HCl + 0.5 mg Leu-Val 0.104 74.5 60.Procaterol-HCl + 1.5 mg Leu-Val 0.073 63.0 61. Procaterol-HCl + 4.5 mgLeu-Val 0.039 53.1 62. Procaterol-HCl + 0.375 mg Leu-Phe 0.168 81.9 63.Procaterol-HCl + 0.5 mg Leu-Phe 0.222 76.1 64. Procaterol-HCl + 0.75 mgLeu-Phe 0.181 79.1 Procaterol-HCl: Procaterol hydrochloride, Leu-Val:leucyl-valine, Leu-Phe: leucyl-phenylalanine

As shown in Table 6, the non-powder-form freeze-dried compositions(freeze-dried cakes), which showed a disintegration index of 0.039 ormore, were easily made into fine particles in the vessel by the airimpact arising through an air speed of about 95 m/sec and an air flowrate of about 295 ml/sec, with it being possible to produce a powderedpreparation suitable for transpulmonary administration.

Example 65

5 μg of procaterol hydrochloride (made by Otsuka Pharmaceutical Co.,Ltd.) and 1.0 mg of valine were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter23 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was calculated. Next, a vessel (trunk diameter 23 mm) filledwith the non-powder-form freeze-dried composition obtained was installedin a self-inhaling type dry powder inhaler designed such that the boreof the air introduction flow path 17 was 4.01 mm and the bore of thesuction flow path 16 was 4.01 mm. This was directly jetted out into anAerosizer (made by Amherst Process Instrument, Inc., USA) fitted with anAerobreather (made by Amherst Process Instrument, Inc., USA; measurementconditions: breath rate: 1 L/min, breath volume: 0.1 L), which is anartificial lung model capable of directly measuring the particle sizedistribution of the particles jetted out (applying an air impact arisingthrough an air speed of about 1 m/sec and an air flow rate of about 17ml/sec to the freeze-dried cake), and the particle size distribution ofthe fine particles jetted out was measured. The mass median aerodynamicdiameter (μm±SD) of the fine particles was calculated from the particlesize distribution. The disintegration index, and the mass medianaerodynamic diameter of the fine particles jetted out from the inhalerare shown in Table 7 for the freeze-dried composition.

TABLE 7 Mass median Freeze-dried Disintegration aerodynamic diametercomposition index (μm ± SD, MMAD) 65.  Procaterol-HCl + valine 0.2731.582 ± 1.552 Procaterol-HCl: Procaterol hydrochloride

As shown in Table 7, the non-powder-form freeze-dried composition(freeze-dried cake), which showed a disintegration index of 0.273, waseasily made into fine particles in the vessel by the above-mentioned airimpact, and moreover the mean particle diameter was less than 5 microns,and hence it was possible to produce a preparation suitable fortranspulmonary administration.

Examples 66 to 70

Insulin (recombinant human insulin crystal, made by Biobras, Brazil;relative activity: 26.4 U/mg) (1 mg, 2 mg), or insulin and any ofvarious carriers as shown in Table 8, was/were made up to 0.2 ml bydissolving in injection distilled water, this was filled into vessels(trunk diameter 18 mm), and freeze-drying was carried out using ashelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form freeze-dried composition(freeze-dried cake) obtained was calculated. Next, as in Examples 38 to48, a vessel (trunk diameter 18 mm) filled with the non-powder-formfreeze-dried composition obtained was installed in a self-inhaling typedry powder inhaler designed such that the bore of the air introductionflow path 17 was 1.99 mm and the bore of the suction flow path 16 was1.99 mm. Using this, the fine particle fraction (%) was calculated witha twin impinger (made by Copley, UK) (applying an air impact arisingthrough an air speed of about 95 m/sec and an air flow rate of about 295ml/sec to the freeze-dried cake). The disintegration index and the fineparticle fraction (%) are shown in Table 8 for each of the freeze-driedcompositions.

TABLE 8 Disintegration Fine particle Freeze-dried composition indexfraction (%) 66.  1 mg insulin 0.159 75.0 67.  1 mg insulin + 1.4 mgleucine 0.145 80.7 68.  1 mg insulin + 1.0 mg valine 0.110 79.4 69.  2mg insulin 0.177 42.4 70.  2 mg insulin + 1.4 mg leucine 0.137 65.1

As can be seen from Table 8, regardless of whether or not a carrier waspresent, the non-powder-form freeze-dried compositions (freeze-driedcakes), which showed a disintegration index of 0.110 or more, wereeasily made into fine particles in the vessel by the above-mentioned airimpact, with it being possible to produce a powdered preparationsuitable for transpulmonary administration.

Examples 71 to 75

1 mg of insulin (recombinant human insulin crystal, made by Biobras,Brazil; relative activity: 26.4 U/mg) and any of various carriers (1.5mg) as shown in Table 9 were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was calculated. Next, a vessel (trunk diameter 18 mm) filledwith the non-powder-form freeze-dried composition obtained was installedin a jet type dry powder inhaler (having a bellows body capable ofsupplying an amount of air of about 20 ml) designed such that the boreof the air jet flow path was 1.2 mm and the bore of the discharge flowpath was 1.8 mm), and as in Examples 1 to 37 this was directly jettedout into an Aerosizer (made by Amherst Process Instrument, Inc., USA)fitted with an Aerobreather (made by Amherst Process Instrument, Inc.,USA; measurement conditions: breath rate: 60 L/min, breath volume: 1 L)(applying an air impact arising through an air speed of about 35 m/secand an air flow rate of about 40 ml/sec to the freeze-dried cake), theparticle size distribution of the fine particles jetted out wasmeasured, and the mass median aerodynamic diameter (μm±SD) wascalculated.

Furthermore, as in Examples 38 to 48, a vessel (trunk diameter 18 mm)filled with the non-powder-form freeze-dried composition obtained wasinstalled in a self-inhaling type dry powder inhaler designed such thatthe bore of the air introduction flow path was 1.99 mm and the bore ofthe suction flow path was 1.99 mm. Using this, the fine particlefraction (%) was calculated with a twin impinger (made by Copley, UK)(applying an air impact arising through an air speed of about 95 m/secand an air flow rate of 295 ml/sec to the freeze-dried cake).

The disintegration index, the mass median aerodynamic diameter (μm±SD)of the fine particles jetted out from the jet type dry powder inhaler,and the fine particle fraction (%) of the fine particles obtained by theself-inhaling type dry powder inhaler are shown in Table 9 for each ofthe freeze-dried compositions.

TABLE 9 Mass median Fine aerodynamic particle    Freeze-driedDisintegration diameter fraction   composition index (μm ± SD, MMAD) (%)71. Insulin + isoleucine 0.124 1.759 ± 1.425 71.1 72. Insulin + leucine0.250 1.954 ± 1.454 74.1 73. Insulin +valine 0.124 2.007 ± 1.438 72.174. Insulin + 0.204 1.872 ± 1.477 62.0 phenylalanine 75. Insulin + 0.1602.239 ± 1.435 61.2 D-mannitol

As shown in Table 9, the non-powder-form freeze-dried compositions(freeze-dried cakes), which showed a disintegration index of 0.124 ormore, were easily made into fine particles in the vessel by the airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec or the air impact arising through an air speedof about 95 m/sec and an air flow rate of 295 ml/sec. Moreover, the meanparticle diameter of the fine particles made by the air impact arisingthrough an air speed of about 95 m/sec and an air flow rate of 295ml/sec was less than 5 microns, and hence it was possible to produce apowdered preparation suitable for transpulmonary administration.

Example 76

500,000 IU of interferon-γ (IFN-γ) (made by Hayashibara BiochemicalLaboratories, Inc., Japan, relative activity: 10,000,000 IU/mg) and thecarrier shown in Table 10 were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form freeze-dried composition (freeze-dried cake)obtained was calculated.

Next, as in Examples 1 to 37, a vessel (trunk diameter 18 mm) filledwith the non-powder-form freeze-dried composition obtained was installedin a jet type dry powder inhaler (having a bellows body capable ofsupplying an amount of air of about 20 ml) designed such that the boreof the air jet flow path was 1.2 mm and the bore of the discharge flowpath was 1.8 mm), jetting was carried out directly into an Aerosizer(made by Amherst Process Instrument, Inc., USA) fitted with anAerobreather (made by Amherst Process Instrument, Inc., USA; measurementconditions: breath rate: 60 L/min, breath volume: 1 L) (applying an airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec to the freeze-dried cake), the particle sizedistribution of the fine particles jetted out was measured, and the massmedian aerodynamic diameter (μm±SD) was calculated. The disintegrationindex and the mass median aerodynamic diameter (μm±SD) of the fineparticles jetted out from the inhaler are shown in Table 10 for thefreeze-dried composition.

TABLE 10 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 76. IFN-γ + 1 mg Phe + 0.336 1.212 ±1.384   0.3 mg Leu + 0.2 mg Arg-HCl Phe: Phenylalanine, Leu: leucine,Arg-HCl: arginine hydrochloride

As can be seen from Table 10, the non-powder-form freeze-driedcomposition (freeze-dried cake), which showed a disintegration index of0.336, was easily made into fine particles in the vessel by the airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec, and moreover the mean particle diameter wasless than 5 microns, and hence it was possible to produce a powderedpreparation suitable for transpulmonary administration.

Examples 77 and 78

10,000,000 IU or 2,500,000 IU of interferon-γ (IFN-γ) (made byHayashibara Biochemical Laboratories, Inc., Japan, relative activity:10,000,000 IU/mg) was made up to 0.5 ml by dissolving in injectiondistilled water, this was filled into vessels (trunk diameter 18 mm),and freeze-drying was carried out using a shelf-type freeze-dryer(Lyovac GT-4, made by Leybold). The disintegration index of thenon-powder-form freeze-dried composition (freeze-dried cake) obtainedwas calculated. Next, as in Examples 1 to 37, a vessel (trunk diameter18 mm) filled with the non-powder-form freeze-dried composition obtainedwas installed in a jet type dry powder inhaler (having a bellows bodycapable of supplying an amount of air of about 20 ml) designed such thatthe bore of the air jet flow path was 1.2 mm and the bore of thedischarge flow path was 1.8 mm, and jetting was carried out directlyinto an Aerosizer (made by Amherst Process Instrument, Inc., USA) fittedwith an Aerobreather (made by Amherst Process Instrument, Inc., USA;measurement conditions: breath rate: 60 L/min, breath volume: 1 L)(applying an air impact arising through an air speed of about 35 m/secand an air flow rate of about 40 ml/sec to the freeze-dried cake), theparticle size distribution of the fine particles jetted out wasmeasured, and the mass median aerodynamic diameter (μm±SD) wascalculated. The disintegration index and the mass median aerodynamicdiameter (μm±SD) of the fine particles jetted out from the inhaler areshown in Table 11 for each of the freeze-dried compositions.

TABLE 11 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 77. 10,000,000 IU of IFN-γ 0.2062.355 ± 1.439 78. 2,500,000 IU of IFN-γ 0.160 2.244 ± 1.514

As shown in Table 11, despite not containing a carrier, thenon-powder-form freeze-dried compositions (freeze-dried cakes), whichshowed a disintegration index of 0.160 or more, were easily made intofine particles in the vessel by the above-mentioned air impact, andmoreover the mean particle diameter was less than 5 microns, and henceit was possible to produce a preparation suitable for transpulmonaryadministration.

Examples 79 to 83

28 μg of pUC19 DNA (2686 bp, made by Otsuka Pharmaceutical Co., Ltd.,hereinafter referred to as ‘pUC19 DNA’), which is a plasmid DNA, and 2.0mg of any of various carriers as shown in Table 12 were made up to 0.5ml by dissolving in injection distilled water, this was filled intovessels (trunk diameter 18 mm), and freeze-drying was carried out usinga shelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form freeze-dried composition(freeze-dried cake) obtained was calculated. Next, as in Examples 71 to78, a vessel (trunk diameter 18 mm) filled with the non-powder-formfreeze-dried composition obtained was installed in a jet type dry powderinhaler (having a bellows body capable of supplying an amount of air ofabout 50 ml) designed such that the bore of the air jet flow path was1.2 mm and the bore of the discharge flow path was 1.8 mm, and jettingwas carried out directly into an Aerosizer (made by Amherst ProcessInstrument, Inc., USA) fitted with an Aerobreather (made by AmherstProcess Instrument, Inc., USA; measurement conditions: breath rate: 60L/min, breath volume: 1 L) (applying an air impact arising through anair speed of about 89 m/sec and an air flow rate of about 100 ml/sec tothe freeze-dried cake), the particle size distribution of the fineparticles jetted out was measured, and the mass median aerodynamicdiameter (μm±SD) was calculated. The disintegration index, and the massmedian aerodynamic diameter of the fine particles jetted out from theinhaler are shown in Table 12 for each of the freeze-dried compositions.

TABLE 12 Mass median aerodynamic   Freeze-dried Disintegration diameter  composition index (μm ± SD, MMAD) 79. pUC19 DNA + isoleucine 0.1032.168 ± 1.586 80. pUC19 DNA + leucine 0.096 1.603 ± 1.580 81. pUC19DNA + valine 0.110 1.789 ± 1.486 82. pUC19 DNA + phenylalanine 0.1491.375 ± 1.545 83. pUC19 DNA + D-mannitol 0.126 1.969 ± 1.503

As shown in Table 12, the non-powder-form freeze-dried compositions(freeze-dried cakes), which showed a disintegration index of 0.096 ormore, were easily made into fine particles in the vessel by the airimpact arising through an air speed of about 89 m/sec and an air flowrate of about 100 ml/sec, and moreover the mean particle diameter wasless than 5 microns, and hence it was possible to produce a powderedpreparation suitable for transpulmonary administration.

Examples 84 to 87

100 μg of an anti-interleukin-1β antibody (anti-IL-1β antibody) (made byOtsuka Pharmaceutical Co., Ltd., Japan) and 2.0 mg of any of variouscarriers as shown in Table 13 were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form cake-like freeze-dried composition (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with the non-powder-form freeze-dried composition obtained wasinstalled in a jet type dry powder inhaler (having a bellows bodycapable of supplying an amount of air of about 20 ml) designed such thatthe bore of the air jet flow path was 1.2 mm and the bore of thedischarge flow path was 1.8 mm, and jetting was carried out directlyinto an Aerosizer (made by Amherst Process Instrument, Inc., USA) fittedwith an Aerobreather (made by Amherst Process Instrument, Inc., USA;measurement conditions: breath rate: 60 L/min, breath volume: 1 L)(applying an air impact arising through an air speed of about 35 m/secand an air flow rate of about 40 ml/sec to the freeze-dried cake), theparticle size distribution of the fine particles jetted out wasmeasured, and the mass median aerodynamic diameter (μm±SD) wascalculated. The disintegration index, and the mass median aerodynamicdiameter (μm±SD) of the fine particles jetted out from the inhaler areshown in Table 13 for each of the freeze-dried compositions.

TABLE 13 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 84. Anti-IL-1β antibody + Ile 0.2721.668 ± 1.434 85. Anti-IL-1β antibody + Leu 0.195 1.681 ± 1.404 86.Anti-IL-1β antibody + Val 0.277 1.890 ± 1.392 87. Anti-IL-1β antibody +Phe 0.358 1.462 ± 1.396 Ile: isoleucine, Leu: leucine, Val: valine, Phe:phenylalanine

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 13, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.195 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Examples 88 to 91

100 μg of an anti-interleukin-1α antibody (anti-IL-1α antibody) (made byOtsuka Pharmaceutical Co., Ltd., Japan) and 2.0 mg of any of variouscarriers as shown in Table 14 were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form cake-like freeze-dried composition (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with the non-powder-form freeze-dried composition obtained wasinstalled in a jet type dry powder inhaler (having a bellows bodycapable of supplying an amount of air of about 20 ml) designed such thatthe bore of the air jet flow path was 1.2 mm and the bore of thedischarge flow path was 1.8 mm, and as in Examples 84 to 87, an airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec was applied to the freeze-dried cake in thevessel, the particle size distribution of the fine particles producedwas measured, and the mass median aerodynamic diameter (μm±SD) wascalculated. The disintegration index, and the mass median aerodynamicdiameter (μm±SD) of the fine particles jetted out from the inhaler areshown in Table 14 for each of the freeze-dried compositions.

TABLE 14 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 88. Anti-IL-1α antibody + Ile 0.2531.515 ± 1.433 89. Anti-IL-1α antibody + Leu 0.204 1.787 ± 1.435 90.Anti-IL-1α antibody + Val 0.257 1.957 ± 1.393 91. Anti-IL-1α antibody +Phe 0.258 1.707 ± 1.426 Ile: isoleucine, Leu: leucine, Val: valine, Phe:phenylalanine

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 14, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.204 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Examples 92 to 95

10 μg of calcitonin (made by Sigma, USA) and 2.0 mg of any of variouscarriers as shown in Table 15 were made up to 0.5 ml by dissolving ininjection distilled water, this was filled into vessels (trunk diameter18 mm), and freeze-drying was carried out using a shelf-typefreeze-dryer (Lyovac GT-4, made by Leybold). The disintegration index ofthe non-powder-form cake-like freeze-dried composition (freeze-driedcake) obtained was calculated. Next, a vessel (trunk diameter 18 mm)filled with the non-powder-form freeze-dried composition obtained wasinstalled in a jet type dry powder inhaler (having a bellows bodycapable of supplying an amount of air of about 20 ml) designed such thatthe bore of the air jet flow path was 1.2 mm and the bore of thedischarge flow path was 1.8 mm, and as in Examples 84 to 87, an airimpact arising through an air speed of about 35 m/sec and an air flowrate of about 40 ml/sec was applied to the freeze-dried cake in thevessel, the particle size distribution of the fine particles producedwas measured, and the mass median aerodynamic diameter (μm±SD) wascalculated. The disintegration index, and the mass median aerodynamicdiameter (μm±SD) of the fine particles jetted out from the inhaler areshown in Table 15 for each of the freeze-dried compositions.

TABLE 15 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 92. Calcitonin + isoleucine 0.2091.531 ± 1.457 93. Calcitonin + leucine 0.273 1.699 ± 1.434 94.Calcitonin + valine 0.248 1.421 ± 1.466 95. Calcitonin + phenylalanine0.150 1.653 ± 1.408

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 15, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.150 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Examples 96 to 100

12 μg of erythropoietin (made by Wako Pure Chemical Industries, Ltd.,Japan) and 2.0 mg of any of various carriers as shown in Table 16 weremade up to 0.5 ml by dissolving in injection distilled water, this wasfilled into vessels (trunk diameter 18 mm), and freeze-drying wascarried out using a shelf-type freeze-dryer (Lyovac GT-4, made byLeybold). The disintegration index of the non-powder-form cake-likefreeze-dried composition (freeze-dried cake) obtained was calculated.Next, a vessel (trunk diameter 18 mm) filled with the non-powder-formfreeze-dried composition obtained was installed in a jet type dry powderinhaler (having a bellows body capable of supplying an amount of air ofabout 20 ml) designed such that the bore of the air jet flow path was1.2 mm and the bore of the discharge flow path was 1.8 mm, and as inExamples 84 to 87, an air impact arising through an air speed of about35 m/sec and an air flow rate of about 40 ml/sec was applied to thefreeze-dried cake in the vessel, the particle size distribution of thefine particles produced was measured, and the mass median aerodynamicdiameter (μm±SD) was calculated. The disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 16 for each of the freeze-driedcompositions.

TABLE 16 Mass median aerodynamic diameter Freeze-dried Disintegration(μm ± SD, composition index MMAD) 96. Erythropoietin + isoleucine 0.2871.214 ± 1.396 97. Erythropoietin + leucine 0.213 1.833 ± 1.429 98.Erythropoietin + valine 0.254 1.670 ± 1.444 99. Erythropoietin +phenylalanine 0.309 1.923 ± 1.447 100. Erythropoietin + D-mannitol 0.1551.795 ± 1.412

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 16, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.155 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Example 101

20 μg of granulocyte colony stimulating factor (G-CSF) (made by EvermoreBio, China) and 2.5 mg of D-mannitol were made up to 0.5 ml bydissolving in injection distilled water, this was filled into vessels(trunk diameter 18 mm), and freeze-drying was carried out using ashelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, a vessel(trunk diameter 18 mm) filled with the non-powder-form freeze-driedcomposition obtained was installed in a jet type dry powder inhaler(having a bellows body capable of supplying an amount of air of about 20ml) designed such that the bore of the air jet flow path was 1.2 mm andthe bore of the discharge flow path was 1.8 mm, and as in Examples 84 to87, an air impact arising through an air speed of about 35 m/sec and anair flow rate of about 40 ml/sec was applied to the freeze-dried cake inthe vessel, the particle size distribution of the fine particlesproduced was measured, and the mass median aerodynamic diameter (μm±SD)was calculated. The disintegration index, and the mass medianaerodynamic diameter (μm±SD) of the fine particles jetted out from theinhaler are shown in Table 17 for the freeze-dried composition.

TABLE 17 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 101. G-CSF + D-mannitol 0.049 1.795± 1.412

The freeze-dried composition obtained was a non-powder-form cake-likemass (freeze-dried cake) at the time of freeze-drying. As can be seenfrom Table 17, the non-powder-form freeze-dried cake, which showed adisintegration index of 0.049, was disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, becoming fine particles of mass median aerodynamicdiameter less than 5 microns, i.e. becoming a powdered preparationsuitable for transpulmonary administration.

Examples 102 to 104

100 μg of growth hormone (made by Wako Pure Chemical Industries, Ltd.,Japan) and any of various carriers as shown in Table 18 were made up to0.5 ml by dissolving in injection distilled water, this was filled intovessels (trunk diameter 18 mm), and freeze-drying was carried out usinga shelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, a vessel(trunk diameter 18 mm) filled with the non-powder-form freeze-driedcomposition obtained was installed in a jet type dry powder inhaler(having a bellows body capable of supplying an amount of air of about 20ml) designed such that the bore of the air jet flow path was 1.2 mm andthe bore of the discharge flow path was 1.8 mm, and as in Examples 84 to87, an air impact arising through an air speed of about 35 m/sec and anair flow rate of about 40 ml/sec was applied to the freeze-dried cake inthe vessel, the particle size distribution of the fine particlesproduced was measured, and the mass median aerodynamic diameter (μm±SD)was calculated. The disintegration index, and the mass medianaerodynamic diameter (μm±SD) of the particles jetted out from theinhaler are shown in Table 18 for each of the freeze-dried compositions.

TABLE 18 Mass median aerodynamic diameter Freeze-dried Disintegration(μm ± SD, composition index MMAD) 102. GH + 1.5 mg Ile + 0.250 1.626 ±1.473 0.1 mg mannitol + 0.02 mg Gly 103. GH + 1.5 mg Val + 0.270 1.675 ±1.461 0.1 mg mannitol + 0.02 mg Gly 104. GH + 1.5 mg Phe + 0.362 1.286 ±1.375 0.1 mg mannitol + 0.02 mg Gly GH: Growth hormone, Ile: isoleucine,Val: valine, Gly: glycine, mannitol: D-mannitol, Phe: phenylalanine

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 18, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.250 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Examples 105 to 107

1 mg of deoxyribonuclease (Dnase) (made by Sigma, USA) and 2 mg of anyof various carriers as shown in Table 19 were made up to 0.5 ml bydissolving in injection distilled water, this was filled into vessels(trunk diameter 18 mm), and freeze-drying was carried out using ashelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, a vessel(trunk diameter 18 mm) filled with the non-powder-form freeze-driedcomposition obtained was installed in a jet type dry powder inhaler(having a bellows body capable of supplying an amount of air of about 20ml) designed such that the bore of the air jet flow path was 1.2 mm andthe bore of the discharge flow path was 1.8 mm, and as in Examples 84 to87, an air impact arising through an air speed of about 35 m/sec and anair flow rate of about 40 ml/sec was applied to the freeze-dried cake inthe vessel, the particle size distribution of the fine particlesproduced was measured, and the mass median aerodynamic diameter (μm±SD)was calculated. The disintegration index, and the mass medianaerodynamic diameter (μm±SD) of the fine particles jetted out from theinhaler are shown in Table 19 for each of the freeze-dried compositions.

TABLE 19 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 105. Dnase + isoleucine 0.142 1.737± 1.452 106. Dnase + valine 0.209 2.014 ± 1.449 107. Dnase +phenylalanine 0.078 2.425 ± 1.462

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 19, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.078 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Examples 108 and 109

10 μg of parathyroid hormone (PTH) (made by Sigma, USA) and 2 mg of anyof various carriers as shown in Table 20 were made up to 0.5 ml bydissolving in injection distilled water, this was filled into vessels(trunk diameter 18 mm), and freeze-drying was carried out using ashelf-type freeze-dryer (Lyovac GT-4, made by Leybold). Thedisintegration index of the non-powder-form cake-like freeze-driedcomposition (freeze-dried cake) obtained was calculated. Next, a vessel(trunk diameter 18 mm) filled with the non-powder-form freeze-driedcomposition obtained was installed in a jet type dry powder inhaler(having a bellows body capable of supplying an amount of air of about 20ml) designed such that the bore of the air jet flow path was 1.2 mm andthe bore of the discharge flow path was 1.8 mm), and as in Examples 84to 87, an air impact arising through an air speed of about 35 m/sec andan air flow rate of about 40 ml/sec was applied to the freeze-dried cakein the vessel, the particle size distribution of the fine particlesproduced was measured, and the mass median aerodynamic diameter (μm±SD)was calculated. The disintegration index, and the mass medianaerodynamic diameter (μm±SD) of the fine particles jetted out from theinhaler are shown in Table 20 for each of the freeze-dried compositions.

TABLE 20 Mass median   Freeze-dried Disintegration aerodynamic diameter  composition index (μm ± SD, MMAD) 108. PTH + phenylalanine 0.273 1.090± 1.346 109. PTH + D-mannitol 0.234 1.603 ± 1.504

Each of the freeze-dried compositions obtained was a non-powder-formcake-like mass (freeze-dried cake) at the time of freeze-drying. As canbe seen from Table 20, the non-powder-form freeze-dried cakes, whichshowed a disintegration index of 0.234 or more, were disintegrated bythe air impact arising through an air speed of about 35 m/sec and an airflow rate of about 40 ml/sec, becoming fine particles of mass medianaerodynamic diameter less than 5 microns, i.e. becoming a powderedpreparation suitable for transpulmonary administration.

Example 110

100 μg of leuprolide (made by Sigma, USA) and 2 mg of phenylalanine weremade up to 0.5 ml by dissolving in injection distilled water, this wasfilled into vessels (trunk diameter 18 mm), and freeze-drying wascarried out using a shelf-type freeze-dryer (Lyovac GT-4, made byLeybold). The disintegration index of the non-powder-form cake-likefreeze-dried composition (freeze-dried cake) obtained was calculated.Next, a vessel (trunk diameter 18 mm) filled with the non-powder-formfreeze-dried composition obtained was installed in a jet type dry powderinhaler (having a bellows body capable of supplying an amount of air ofabout 20 ml) designed such that the bore of the air jet flow path was1.2 mm and the bore of the discharge flow path was 1.8 mm, and as inExamples 84 to 87, an air impact arising through an air speed of about35 m/sec and an air flow rate of about 40 ml/sec was applied to thefreeze-dried cake in the vessel, the particle size distribution of thefine particles produced was measured, and the mass median aerodynamicdiameter (μm±SD) was calculated. The disintegration index, and the massmedian aerodynamic diameter (μm±SD) of the fine particles jetted outfrom the inhaler are shown in Table 21 for the freeze-dried composition.

TABLE 21 Mass median   Freeze-dried aerodynamic diameter   compositionDisintegration index (μm ± SD, MMAD) 110. Leuprolide + Phe 0.358 1.115 ±1.350 Phe: phenylalanine

The freeze-dried composition obtained was a non-powder-form cake-likemass (freeze-dried cake) at the time of freeze-drying. As can be seenfrom Table 21, the non-powder-form freeze-dried cake, which showed adisintegration index of 0.358, was disintegrated by the air impactarising through an air speed of about 35 m/sec and an air flow rate ofabout 40 ml/sec, becoming fine particles of mass median aerodynamicdiameter less than 5 microns, i.e. becoming a powdered preparationsuitable for transpulmonary administration.

INDUSTRIAL APPLICABILITY

According to the dry powder inhalation system for transpulmonaryadministration of the present invention, a freeze-dried composition canbe made into fine particles down to a size necessary for delivery intothe lungs, and moreover administration of the fine particles into thelungs through inhalation is possible. That is, according to the drypowder inhalation system for transpulmonary administration of thepresent invention, a freeze-dried composition that has been prepared ina non-powder form can be made into fine particles at the time of use(the time of administration), and administered through inhalation at thesame time, and hence a special operation for making the preparation intofine particles becomes unnecessary. Consequently, according to the drypowder inhalation system for transpulmonary administration (preparationsystem) of the present invention, there is no risk of loss during themanufacturing process (deactivation of the drug or collection lossthrough a filling operation) or loss during storage (for exampledeactivation of the drug due to being stored in a fine particle form),or contamination with impurities during the manufacturing process; adesired fixed amount can thus be administered stably. This is useful inparticular with preparations having as an active ingredient a generallyexpensive pharmacologically active substance such as a protein or apeptide.

The proportion of effective particles (fine particle fraction) attainedby the dry powder inhalation system for transpulmonary administration ofthe invention is at least 10%, and can be increased to at least 20%, atleast 25%, at least 30% or at least 35%. U.S. Pat. No. 6,153,224indicates that, with many of prior art dry powder inhalers, theproportion of the active ingredient (particles) to adhere to the lowerportions of the lungs is only about 10% of the amount of the activeingredient inhaled. Further, Japanese Unexamined Patent Publication No.2001-151673 states that the amount of an inhalation powder preparationreaching the lungs (lung reaching proportion) is generally about 10% ofthe drug discharged from the preparation. Therefore, the dry powderinhalation system of the invention is valuable in that it is capable ofachieving a higher proportion of effective particles (fine particlefraction) than prior art powder inhalation preparations.

According to the freeze-dried composition and jet type dry powderinhaler of the present invention, the freeze-dried composition can bemade into fine particles merely by jetting air into the vessel from theair jet flow path using the air pressure-feeding means and thus applyinga slight air impact to the freeze-dried composition. The making intofine particles can thus be carried out at the time of use with an drypowder inhaler having a simple structure and moreover with simplehandling. Moreover, because the dry powder inhaler has a simplestructure, it can be produced with a low manufacturing cost, and hencemass distribution is possible.

Moreover, according to the jet type dry powder inhaler, by adjusting thespeed of compression of the air pressure-feeding means such as a bellowsbody, the amount sucked in of the aerosol (powdered preparation) can beadjusted in accordance with the respiratory ability of the user.Moreover, by using a single integrated needle part, the operation ofpiercing the stopper of the vessel with the needle part becomes simple.

Furthermore, according to the self-inhaling type dry powder inhaler, thefreeze-dried composition can be made into an aerosol (made into fineparticles) through an air impact being generated by the inhalationpressure of the user, and hence the making into fine particles andadministration into the lungs of the freeze-dried composition can becarried out at the same time as the user inhaling, and thus it can beexpected that the drug will be administered in a stable amount with noloss. Moreover, a separate special operation for making into an aerosol(making into fine particles) is unnecessary, and hence handling is easy.Moreover, as with the jet type, by using a single integrated needlepart, the operation of piercing the elastic port stopper of the vesselwith the needle part becomes simple.

According to the dry powder inhaler of the present invention, bypiercing the stopper of the vessel with the tip of the needle parthaving the suction flow path and the air introduction flow path, and airin the vessel then being sucked in from the suction port by theinhalation pressure of the user (patient), air can be made to flow intothe vessel from the air introduction flow path of the needle part, thusapplying an air impact to the freeze-dried composition, and thefreeze-dried composition that has been made into a powder can be suckedin from the vessel.

Moreover, in the case of the dry powder inhaler of the present inventiondisclosed as Embodiment 4 in particular, the following effects areexhibited.

When trying to apply an effective air impact to the freeze-driedcomposition and suck the powder-form freeze-dried composition that hasbeen made into fine particles from the vessel, the cross-sectional areasof the suction flow path and the air introduction flow path must be madelarge, and hence the diameter of the needle part must be made large.

However, in the case of piercing a needle part having a large diameterthrough the stopper, it becomes necessary to hold the vessel securely,and in this state move the vessel towards the needle tip withoutdeviating away from the axis of the needle part, and push the stopperagainst the needle tip with a large force.

As described above, the dry powder inhaler of the present invention thushas a holder part that holds the vessel, a guide part of the holderpart, and a holder operating part having a mechanism part and anoperating member that operates the mechanism part. Therefore, by holdingthe vessel with the holder part, moving the vessel along the axis of theneedle part following the guide part towards the needle tip, andoperating the operating member, it is thus possible to pierce the needlepart through the stopper of the vessel using a relatively low force.

In this way, according to the dry powder inhaler of the presentinvention, the stopper of the vessel can be pierced by the needle parteasily and reliably.

Moreover, if a constitution is adopted in which the housing is formed ina tubular shape, the suction port is formed at a tip part of thehousing, a housing chamber for the vessel is formed in the housing, theneedle part is disposed in the housing so that the needle tip pointstowards the housing chamber, an introduction port for introducingoutside air that communicates with the air introduction flow path of theneedle part is provided in a wall of the housing, and the holder part isadvanced and retreated in the axial direction of the housing in thehousing chamber using the holder operating part, then a pencil-shapeddry powder inhaler can be formed, which is easy to use and convenientlyportable.

Moreover, if the constitution is made to be such that the housing isformed from a housing main body having a removal/insertion port for thevessel in a position in which the holder part is retreated, and a lidfor the removal/insertion port that is connected to the housing mainbody by a hinge, the holder operating part has a mechanism part whichmoves the holder part forwards when the lid is pushed down and theremoval/insertion port closed, and moves the holder part backwards whenthe lid is lifted up and the removal/insertion port opened, and the lidis used as the operating member of the mechanism part, then themechanism part of the holder operating part can be simplified and in themanufacturing cost. Moreover, the removal/insertion port of the vesselcan be closed at the same time as piercing the stopper of the vesselwith the needle tip, and hence use becomes easier.

1. A method of making a non-powder-form freeze-dried compositioncomprising: at least partially filing a vessel with a solution; andfreeze drying the solution in the vessel to form the non-powder-formfreeze-dried composition; wherein the non-powder-form freeze-driedcomposition has at least the following properties: a disintegrationindex greater than or equal to 0.015; and the non-powder-formfreeze-dried composition becomes fine particles upon receiving airimpact at an air speed greater than or equal to 1 meter/second and anair flow rate greater than or equal to 17 milliliters/second; andwherein the fine particles have: a mean particle diameter less than orequal to 1×10⁻⁵ meters; or a fine particle fraction greater than orequal to 10%; or a mean particle diameter less than or equal to 1×10⁻⁵meters and a fine particle fraction greater than or equal to 10%.
 2. Themethod of claim 1, wherein after making the composition, the vessel issealed.
 3. The method of claim 1, wherein the disintegration index isgreater than or equal to 0.02.
 4. The method of claim 1, wherein thedisintegration index is less than or equal to 1.5.
 5. The method ofclaim 1, wherein the air speed is greater than or equal to 2meters/second.
 6. The method of claim 1, wherein the air speed is lessthan or equal to 300 meters/second.
 7. The method of claim 1, whereinthe air flow rate is greater than or equal to 20 milliliters/second. 8.The method of claim 1, wherein the air flow rate is less than or equalto 15 liters/second.
 9. The method of claim 1, wherein the fineparticles have: a mean particle diameter less than or equal to 5×10⁻⁶meters; or a fine particle fraction greater than or equal to 20%; or amean particle diameter less than or equal to 5×10⁻⁶ meters and a fineparticle fraction greater than or equal to 20%.
 10. The method of claim1, wherein the fine particle fraction is greater than or equal to 35%.11. The method of claim 1, wherein the composition is water soluble. 12.The method of claim 1, wherein the composition comprises at least onecarrier.
 13. The method of claim 12, wherein the at least one carrier isselected from: amino acids, dipeptides, tripeptides, and/or saccharides.14. The method of claim 1, wherein the composition comprises at leastone additive.
 15. The method of claim 1, wherein the compositioncomprises: at least one active ingredient; one or more carriers; and atleast one additive.
 16. The method of claim 14 or 15, wherein the atleast one additive comprises one or more: surfactants; and/or bufferingagents.
 17. The method of claim 1, wherein the composition contains onlya single dose of at least one active ingredient.
 18. The method of claim1, wherein the composition contains two doses of at least one activeingredient.
 19. The method of claim 1, wherein the composition containsa plurality of doses of at least one active ingredient.
 20. The methodof claim 1, wherein the composition contains only a single dose of aplurality of active ingredients.
 21. The method of claim 1, wherein thecomposition contains a plurality of active ingredients, and wherein thecomposition contains two doses of the plurality of active ingredients.22. The method of claim 1, wherein the composition contains a pluralityof active ingredients, and wherein the composition contains more thanone dose of the plurality of active ingredients.
 23. A non-powder-formfreeze-dried composition made by the method of claim
 1. 24. Anon-powder-form freeze-dried composition made by the method of claim 17.25. A method of making a dry powder for transpulmonary administration,comprising: directing air at an air speed greater than or equal to 1meter/second and an air flow rate greater than or equal to 17milliliters/second onto a non-powder-form freeze-dried composition toproduce fine particles of dry powder; wherein the non-powder-formfreeze-dried composition has a disintegration index greater than orequal to 0.015, wherein the non-powder-form freeze-dried composition ismade into fine particles when it receives air impact at an air speedgreater than or equal to 1 meter/second and an air flow rate greaterthan or equal to 17 milliliters/second, and wherein the fine particleshave: a mean particle diameter less than or equal to 1×10⁻⁵ meters; or afine particle fraction greater than or equal to 10%; or a mean particlediameter less than or equal to 1×10⁻⁵ meters and a fine particlefraction greater than or equal to 10%.
 26. The method of claim 25,wherein the composition is contained in a vessel.
 27. The method ofclaim 25, wherein the disintegration index is greater than or equal to0.02.
 28. The method of claim 25, wherein the air speed is greater thanor equal to 2 meters/second.
 29. The method of claim 25, wherein the airflow rate is greater than or equal to 20 milliliters/second.
 30. Themethod of claim 25, wherein the fine particles have: a mean particlediameter less than or equal to 5×10⁻⁶ meters; or a fine particlefraction greater than or equal to 20%; or a mean particle diameter lessthan or equal to 5×10⁻⁶ meters and a fine particle fraction greater thanor equal to 20%.
 31. A method of transpulmonary administrationcomprising: directing air at an air speed greater than or equal to 1meter/second and an air flow rate greater than or equal to 17milliliters/second onto a non-powder-form freeze-dried composition toproduce fine particles; and inhaling the fine particles; wherein thenon-powder-form freeze-dried composition has a disintegration indexgreater than or equal to 0.015, wherein the non-powder-form freeze-driedcomposition is made into the fine particles by receiving air impact atan air speed greater than or equal to 1 meter/second and an air flowrate greater than or equal to 17 milliliters/second, and wherein thefine particles have: a mean particle diameter less than or equal to1×10⁻⁵ meters; or a fine particle fraction greater than or equal to 10%;or a mean particle diameter less than or equal to 1×10⁻⁵ meters and afine particle fraction greater than or equal to 10%.
 32. The method ofclaim 31, wherein the composition is contained in a vessel.
 33. Themethod of claim 32, wherein the vessel is associated with a dry powderinhaler comprising: an inlet flow path; and an outlet flow path; whereinthe air flows through the inlet flow path to impact the non-powder-formfreeze-dried composition in the vessel.
 34. The method of claim 33,wherein the air flows from a source of pressurized air associated withthe inlet flow path to impact the non-powder-form freeze-driedcomposition in the vessel.
 35. The method of claim 33, wherein theoutlet flow path is associated with an inhalation port, wherein theinhaling is conducted through the inhalation port and causes a negativepressure in the outlet flow path, wherein the negative pressure causesair from the inlet flow path to impact the non-powder-form freeze-driedcomposition in the vessel, and wherein at least some air from the inletflow path and substantially all of the fine particles move from thevessel to the inhalation port via the outlet flow path.
 36. A method oftranspulmonary administration comprising: making fine particles from anon-powder-form freeze-dried composition; and administering the fineparticles to an individual by inhalation; wherein the non-powder-formfreeze-dried composition has a disintegration index greater than orequal to 0.015, wherein the non-powder-form freeze-dried composition ismade into the fine particles by receiving air impact at an air speedgreater than or equal to 1 meter/second and an air flow rate greaterthan or equal to 17 milliliters/second, and wherein the fine particlescomprise: a mean particle diameter less than or equal to 1×10⁻⁵ meters;or a fine particle fraction greater than or equal to 10%; or a meanparticle diameter less than or equal to 1×10⁻⁵ meters and a fineparticle fraction greater than or equal to 10%.
 37. The method of claim36, wherein the non-powder-form freeze-dried composition comprises: oneor more active ingredients; one or more carriers; and at least oneadditive.
 38. The method of claim 36, wherein the non-powder-formfreeze-dried composition comprises a single dose of one or more activeingredients.
 39. The method of claim 36, wherein the non-powder-formfreeze-dried composition comprises a plurality of doses of one or moreactive ingredients.